Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders

ABSTRACT

The present invention is directed to novel hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives of the general formula 
                         
wherein all variables are as defined herein, useful in the treatment of disorders and conditions mediated by the ORL-1 G-protein coupled receptor. More particularly, the compounds of the present invention are useful in the treatment of disorders and conditions such as anxiety, depression, panic, dementia, mania, bipolar disorder, substance abuse, neuropathic pain, acute pain, chronic pain, migraine, asthma, cough, psychosis, schizophrenia, epilepsy, hypertension, obesity, eating disorders, cravings, diabetes, cardiac arrhythmia, irritable bowel syndrome, Crohn&#39;s disease, urinary incontinence, adrenal disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), Alzheimer&#39;s disease, for improved cognition or memory and for mood stabilization.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/656,934 filed on Sep. 5, 2003 now U.S. Pat. No. 7,081,463, whichclaims benefit of nonprovisional of U.S. Application No. 60/409,134filed on Sep. 9, 2002, the complete disclosures of aforesaidapplications being incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is directed to novel hydroxy alkyl substituted1,3,8-triazaspiro[4.5]decan-4-one derivatives useful in the treatment ofdisorders and conditions mediated by the ORL-1 G-protein coupledreceptor. More particularly, the compounds of the present invention areuseful in the treatment of disorders and conditions such as anxiety,depression, panic, mania, dementia, bipolar disorder, substance abuse,neuropathic pain, acute pain, chronic pain, migraine, asthma, cough,psychosis, schizophrenia, epilepsy, hypertension, obesity, eatingdisorders, cravings, diabetes, cardiac arrhythmia, irritable bowelsyndrome, Crohn's disease, urinary incontinence, adrenal disorders,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), Alzheimer's disease, for improved cognition or memoryand for mood stabilization.

BACKGROUND OF THE INVENTION

The ORL-1 (orphan opioid receptor) G-protein coupled receptor, alsoknown as the nociceptin receptor, was first reported in 1994, and wasdiscovered based on its homology with the classic delta- (OP-1), mu-(OP-3), and kappa- (OP-2) opioid receptors. The ORL-1 G-protein coupledreceptor does not bind opioid ligands with high affinity. The amino acidsequence of ORL-1 is 47% identical to the opioid receptors overall, and64% identical in the transmembrane domains. (Nature, 1995, 377, 532.)

The endogenous ligand of ORL-1, known as nociceptin, a highly basic 17amino acid peptide, was isolated from tissue extracts in 1995. It wasnamed both nociceptin, because it increased sensitivity to pain wheninjected into mouse brain, and orphanin FQ (OFQ) because of the terminalphenylalanine (F) and glutamine (Q) residues that flank the peptide onthe N- and C-termini respectively. (WO97/07212)

Nociceptin binding to ORL-1 receptors causes inhibition of cAMPsynthesis, inhibition of voltage-gated calcium channels, and activationof potassium conductance. In vivo, nociceptin produces a variety ofpharmacological effects that at times oppose those of the opioids,including hyperalgesia and inhibition of morphine-induced analgesia.Mutant mice lacking nociceptin receptors show better performance inlearning and memory tasks. These mutant mice also have normal responsesto painful stimuli.

The ORL-1 receptor is widely distributed/expressed throughout the humanbody, including in the brain and spinal cord. In the spinal cord, theORL-1 receptor exists in both the dorsal and ventral horns, andprecursor mRNA has been found in the superficial lamina of the dorsalhorn, where primary afferent fibers of nociceptors terminate. Therefore,the ORL-1 has an important role in nociception transmission in thespinal cord. This was confirmed in recent studies wherein nociceptin,when given to mice by i.c.v. injection, induced hyperalgesia anddecreased locomotor activity. (Brit. J. Pharmacol. 2000, 129, 1261.)

Ito, et al., in EP 0997464 disclose 1,3,8-triazaspiro[4.5]decan-4-onecompounds as ORL-1 receptor agonists, useful as analgesics or the likein mammalian subjects.

Hohlweg et al., in PCT publication WO 01/36418 disclosetriazaspirodecanones with high affinity for opioid receptor subtypesuseful in the treatment of migraine, non-insulin dependent diabetesmellitus, sepsis, inflammation, incontinence and/or vasomotordisturbances.

Tulshian et al. in PCT publication WO00/06545 disclose high affinityligands for the nociceptin receptor ORL-1 and the use of said compoundsas nociceptin receptor inhibitors useful in the treatment of pain,anxiety, cough, asthma, depression and alcohol abuse.

Higgins, et al., in European Forum of Neuroscience 2000, Brighton, U.K.,Jun. 24-28, 2000, Poster 077.22 disclosed,8-[(1R,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-oneuseful as cognition enhancers.

We now describe novel small molecule modulators of the ORL-1 receptor,useful for the treatment of disorders and conditions mediated by theORL-1 receptor, such as anxiety, depression, panic, dementia, mania,bipolar disorder, substance abuse, neuropathic pain, acute pain, chronicpain, migraine, asthma, cough, psychosis, schizophrenia, epilepsy,hypertension, obesity, eating disorders, cravings, diabetes, cardiacarrhythmia, irritable bowel syndrome, Crohn's disease, urinaryincontinence, adrenal disorders, attention deficit disorder (ADD),attention deficit hyperactivity disorders (ADHD), Alzheimer's disease,for improved cognition or memory and for mood stabilization.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of the general formula(I)

wherein

R⁰ is selected from the group consisting of

each R^(A) and R^(B) is independently selected from the group consistingof hydrogen and C₁₋₄alkyl;

each R^(C) and R^(D) is independently selected from the group consistingof hydrogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano,N(R^(E))₂, aryl, arC₁₋₄alkyl, heteroaryl or heterocycloalkyl; whereinthe aryl, arC₁₋₄alkyl, heteroaryl or heterocycloalkyl substituent isoptionally substituted with one or more substituents independentlyselected from hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano orN(R^(E))₂;

each R^(E) is independently selected from the group consisting ofhydrogen and C₁₋₄alkyl;

X is selected from the group consisting of —NR¹R², —C(O)—NR¹R²,—NR¹—C(O)—R², —OR¹, —SR¹, —SOR¹, —SO₂R¹, —S—(C₂₋₄alkyl)-NR¹R²,—S—(C₂₋₄alkyl)-NR¹—C(O)O—C(CH₃)₃, —SO—(C₁₋₄alkyl)-NR¹R² and—SO₂—(C₁₋₄alkyl)-NR¹R²; wherein the alkyl portion of the—S—(C₂₋₄alkyl)-NR¹R², —SO—(C₁₋₄alkyl)-NR¹R² or —SO₂—(C₁₋₄alkyl)-NR¹R²group is optionally substituted with one or more substituentsindependently selected from carboxy, hydroxy, hydroxyC₁₋₄alkyl,C₁₋₄alkyl, C₁₋₄alkoxycarbonyl or —CONR¹R²;

each R¹ and R² is independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, C₁₋₈alkoxy, C₁₋₈alkoxycarbonyl, cycloalkyl,cycloalkyl-C₁₋₄alkyl, partially unsaturated carbocyclyl, partiallyunsaturated carbocyclyl-C₁₋₄alkyl, aryl, arC₁₋₄alkyl, arC₁₋₄alkoxy,heteroaryl, heteroaryl-C₁₋₄alkyl, heterocycloalkyl,heterocycloalkyl-C₁₋₄alkyl, —C(O)—C₁₋₆alkyl, —C(O)-aryl,—C(O)-arC₁₋₄alkyl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl,—C(O)O-cycloalkyl and —C(O)O-aryl, —C(O)O-arC₁₋₄alkyl, —C(O)O-(partiallyunsaturated carbocyclyl), C(O)-heteroaryl, —C(O)O-heterocycloalkyl;wherein the C₁₋₈alkyl, cycloalkyl, partially unsaturated carbocyclyl,aryl, arC₁₋₄alkyl, heteroaryl or heterocycloalkyl group, whether aloneor part of a substituent group, is optionally substituted with one ormore substituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano,C(O)—C₁₋₄alkyl, C₁₋₄alkoxycarbonyl, N(R^(E))₂, N(R^(E))₂—C₁₋₄alkyl,N(R^(E))—C(O)C(CH₃)₃, —C₁₋₄alkyl-N(R^(E))C(O)O—C₁₋₄alkyl and—N(R^(E))C(O)O—C₁₋₄alkyl, aryl, aryloxy, cycloalkyl, heteroaryl, arylsubstituted heteroarylaminosulfonyl or C₁₋₆alkylthio;

alternatively when R¹ and R² are both bound to the same nitrogen atom,R¹ and R² are taken together with the nitrogen atom to which they arebound to form a heteroaryl or heterocycloalkyl group; wherein theheteroaryl or heterocycloalkyl group is optionally substituted with oneor more substituents independently selected from halogen, hydroxy,carboxy, C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, cyano,N(R^(E))₂, aryl, arC₁₋₄alkyl, heteroaryl, heterocycloalkyl,di(C₁₋₆)alkylamino-carbonyl, C₁₋₄alkoxycarbonyl-N(R^(E))— orarylamino-C₁₋₄alkyl; wherein the aryl, arC₁₋₄alkyl, heteroaryl orheterocycloalkyl substituent is optionally further substituted with oneor more substituents independently selected from halogen, hydroxy,carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,nitro, cyano, N(R^(E))₂, phenyl or substituted phenyl; wherein thesubstituents on the phenyl are one or more independently selected fromhalogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl,trifluoromethoxy, nitro, cyano or N(R^(E))₂;

R³ is selected from the group consisting of aryl, arC₁₋₆alkyl andheteroaryl; wherein the aryl, arC₁₋₆alkyl or heteroaryl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^(E))₂;

n is an integer from 0 to 2;

R⁴ is selected from the group consisting of hydroxy, C₁₋₄alkyl andhydroxy substituted C₁₋₄alkyl;

m is an integer from 0 to 1;

L¹ is selected from the group consisting of C₁₋₆alkyl and C₃₋₆alkenyl;wherein the double bond of the C₃₋₆alkenyl group is at least one carbonatom removed from the attachment point to the N atom; and wherein theC₁₋₆alkyl or C₃₋₆alkenyl group is optionally substituted with one to twosubstituents independently selected from hydroxy, fluoro, C₁₋₆alkyl,fluorinated C₁₋₆alkyl or C₁₋₆alkoxy;

is selected from the group consisting of cycloalkyl, partiallyunsaturated carbocyclyl, aryl, heteroaryl and heterocycloalkyl;

p is an integer from 0 to 5;

R⁵ is selected from the group consisting of hydroxy, carboxy, halogen,C₁₋₆alkyl, hydroxy substituted C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano,NR¹R², trifluoromethyl, trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO—NR¹R²,—S₂—NR¹R² and —C(O)—NR¹R²;

q is an integer from 0 to 1;

R⁶ is selected from the group consisting of -(L²)₀₋₁-R⁷;

L² is selected from the group consisting of —C₁₋₆alkyl-, —C₂₋₄alkenyl-,—C₂₋₆alkynyl-, —O—, —S—, —NH—, —N(C₁₋₄alkyl)-, —C₁₋₆alkyl-O—,—C₁₋₆alkyl-S—, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —O—C₂₋₆alkyl-O—,—S—C₂₋₆alkyl-S—, —SO₂—, —SO₂NH—, —SO₂N(C₁₋₄alkyl)-, —NH—SO₂—,—N(C₁₋₄alkyl)-SO₂—, —C(O)—O— and —O—C(O)—;

R⁷ is selected from the group consisting of aryl, partially unsaturatedcarbocyclyl, cycloalkyl, heteroaryl and heterocycloalkyl; wherein thearyl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl orheterocycloalkyl group is optionally substituted with one or moresubstituents independently selected from hydroxy, carboxy, halogen,C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, N(R^(E))₂, trifluoromethyl,trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO₂—N(R^(E))₂ and—C(O)—N(R^(E))₂;

or a pharmaceutically acceptable salt thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedabove. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating disorders andconditions mediated by the ORL-1 receptor in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove.

An example of the invention is a method of treating a condition selectedfrom the group consisting of anxiety, depression, panic, mania,dementia, bipolar disorder, substance abuse, neuropathic pain, acutepain, chronic pain migraine, asthma, cough, psychosis, schizophrenia,epilepsy, hypertension, obesity, eating disorders, cravings, diabetes,cardiac arrhythmia, irritable bowel syndrome, Crohn's disease, urinaryincontinence, adrenal disorders, attention deficit disorder (ADD),attention deficit hyperactivity disorder (ADHD), Alzheimer's disease,for improved cognition or memory and for mood stabilization, in asubject in need thereof comprising administering to the subject atherapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)anxiety, (b) depression, (c) panic, (d) mania, (e) dementia, (f) bipolardisorder, (g) substance abuse (h) neuropathic pain, (i) acute pain, (j)chronic pain, (k) migraine, (l) asthma, (m) cough, (n) psychosis, (o)schizophrenia, (p) epilepsy, (q) hypertension, (r) obesity, (s) eatingdisorders, (t) cravings, (u) diabetes), (v) cardiac arrhythmia, (w)irritable bowel syndrome, (x) Crohn's disease, (uy) urinaryincontinence, (z) adrenal disorders, (aa) attention deficit disorder(ADD), (bb) attention deficit hyperactivity disorder (ADHD), (cc)Alzheimer's disease, for (dd) improved cognition, (ee) improved memoryand (ff) mood stabilization, in a subject in need thereof.

The present invention is further directed to a compound of formula (E)

wherein

R³ is selected from the group consisting of aryl, arC₁₋₆alkyl andheteroaryl; wherein the aryl, arC₁₋₆alkyl or heteroaryl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^(E))₂;

wherein each R^(E) is independently selected from hydrogen or C₁₋₄alkyl;

n is an integer from 0 to 2;

R⁴ is selected from the group consisting of hydroxy, C₁₋₄alkyl andhydroxy substituted C₁₋₄alkyl;

Y is selected from the group consisting of hydrogen, C₁₋₄alkyl,t-butoxycarbonyl and

m is an integer from 0 to 1;

L¹ is selected from the group consisting of C₁₋₆alkyl and C₃₋₆alkenyl;wherein the double bond of the C₃₋₆alkenyl group is at least one carbonatom removed from the attachment point to the N atom; and wherein theC₁₋₆alkyl or C₃₋₆alkenyl group is optionally substituted with one to twosubstituents independently selected from hydroxy, fluoro, C₁₋₆alkyl,fluorinated C₁₋₆alkyl or C₁₋₆alkoxy;

is selected from the group consisting of cycloalkyl, partiallyunsaturated carbocyclyl, aryl, heteroaryl and heterocycloalkyl;

p is an integer from 0 to 5;

R⁵ is selected from the group consisting of hydroxy, carboxy, halogen,C₁₋₆alkyl, hydroxy substituted C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano,NR¹R², trifluoromethyl, trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO—NR¹R²,—SO₂—NR¹R² and —C(O)—NR¹R²;

q is an integer from 0 to 1;

R⁶ is selected from the group consisting of -(L²)₀₋₁-R⁷;

L² is selected from the group consisting of —C₁₋₆alkyl-, —C₂₋₄alkenyl-,—C₂₋₆alkynyl-, —O—, —S—, —NH—, —N(C₁₋₄alkyl)-, —C₁₋₆alkyl-O—,—C₁₋₆alkyl-S—, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —O—C₂₋₆alkyl-O—,—S—C₂₋₆alkyl-S—, —SO₂—, —SO₂NH—, —SO₂N(C₁₋₄alkyl)-, —NH—SO₂—,—N(C₁₋₄alkyl)-SO₂—, —C(O)—O— and —O—C(O)—;

R⁷ is selected from the group consisting of aryl, partially unsaturatedcarbocyclyl, cycloalkyl, heteroaryl and heterocycloalkyl; wherein thearyl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl orheterocycloalkyl group is optionally substituted with one or moresubstituents independently selected from hydroxy, carboxy, halogen,C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, N(R^(E))₂, trifluoromethyl,trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO₂—N(R^(E))₂ and—C(O)—N(R^(E))₂;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides hydroxy alkyl substituted1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatmentof disorders and conditions mediated by the ORL-1 receptor. Moreparticularly, the compounds of the present invention are of the generalformula (I)

wherein R⁰, R³, n, R⁴, m, L¹,

p, R⁵, q and R⁶ are as herein defined, or a pharmaceutically acceptablesalt thereof. The compounds of formula (I) are useful in the treatmentof disorders mediated by the ORL-1 receptor. The compound of formula (I)are further useful for the treatment of disorders associated with theadrenal gland.

More particularly, the compound of formula (I) are useful in thetreatment of anxiety, depression, panic, mania, dementia, bipolardisorder, substance abuse, neuropathic pain, acute pain, chronic painmigraine, asthma, cough, psychosis, schizophrenia, epilepsy,hypertension, obesity, eating disorders, cravings, diabetes, cardiacarrhythmia, irritable bowel syndrome, Crohn's disease, urinaryincontinence, adrenal disorders, attention deficit disorder (ADD),attention deficit hyperactivity disorder (ADHD), Alzheimer's disease,for improved cognition or memory and for mood stabilization. Preferably,the compounds of formula (I) are useful in the treatment of anxiety,depression, substance abuse, neuropathic pain, acute pain, chronic pain,migraine, cough, hypertension, cardiac arrhythmia, irritable bowelsyndrome and Crohn's disease.

In an embodiment of the present invention are compounds of formula (I)wherein R⁰ is selected from the group consisting of

each R^(A) and R^(B) is independently selected from the group consistingof hydrogen and C₁₋₄alkyl;

each R^(C) and R^(D) is independently selected from the group consistingof hydrogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano,N(R^(E))₂, aryl, arC₁₋₄alkyl, heteroaryl or heterocycloalkyl; whereinthe aryl, arC₁₋₄alkyl, heteroaryl or heterocycloalkyl substituent isoptionally substituted with one or more substituents independentlyselected from hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano orN(R^(E))₂;

each R^(E) is independently selected from the group consisting ofhydrogen and C₁₋₄alkyl;

X is selected from the group consisting of —NR¹R², —C(O)—NR¹R²,—NR¹—C(O)—R², —OR¹, —SR¹, —SOR¹, —SO₂R¹, —S—(C₂₋₄alkyl)-NR¹R²,—S—(C₂₋₄alkyl)-NR¹—C(O)O—C(CH₃)₃, —SO—(C₁₋₄alkyl)-NR¹R² and—SO₂—(C₁₋₄alkyl)-NR¹R²; wherein the alkyl portion of the—S—(C₂₋₄alkyl)-NR¹R², —SO—(C₁₋₄alkyl)-NR¹R² or —SO₂—(C₁₋₄alkyl)-NR¹R²group is optionally substituted with one or more substituentsindependently selected from carboxy, hydroxy, hydroxyC₁₋₄alkyl,C₁₋₄alkyl, C₁₋₄alkoxycarbonyl or —CONR¹R²;

each R¹ and R² is independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, C₁₋₈alkoxy, cycloalkyl, cycloalkyl-C₁₋₄alkyl,partially unsaturated carbocyclyl, aryl, arC₁₋₄alkyl, arC₁₋₄alkoxy,heteroaryl, heteroaryl-C₁₋₄alkyl, heterocycloalkyl,heterocycloalkyl-C₁₋₄alkyl, —C(O)—C₁₋₆alkyl, —C(O)-aryl,—C(O)-arC₁₋₄alkyl, —C(O)-heteroaryl and —C(O)-heterocycloalkyl; whereinthe C₁₋₈alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl,arC₁₋₄alkyl, heteroaryl or heterocycloalkyl group, whether alone or partof a substituent group, is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano,C(O)—C₁₋₄alkyl, C₁₋₄alkoxycarbonyl, N(R^(E))₂, N(R^(E))₂—C₁₋₄alkyl,N(R^(E))—C(O)C(CH₃)₃, aryl, aryloxy, cycloalkyl, heteroaryl, arylsubstituted heteroarylaminosulfonyl or C₁₋₆alkylthio;

alternatively when R¹ and R² are both bound to the same nitrogen atom,R¹ and R² are taken together with the nitrogen atom to which they arebound to form a heteroaryl or heterocycloalkyl group; wherein theheteroaryl or heterocycloalkyl group is optionally substituted with oneor more substituents independently selected from halogen, hydroxy,carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, trifluoromethyl,trifluoromethoxy, nitro, cyano, N(R^(E))₂, aryl, arC₁₋₄alkyl,heteroaryl, heterocycloalkyl, di(C₁₋₆)alkylamino-carbonyl,t-butoxycarbonyl or arylamino-C₁₋₄alkyl; wherein the aryl, arC₁₋₄alkyl,heteroaryl or heterocycloalkyl substituent is optionally furthersubstituted with one or more substituents independently selected fromhalogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl,trifluoromethoxy, nitro, cyano, N(R^(E))₂ or substituted phenyl; whereinthe substituents on the phenyl are one or more independently selectedfrom halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl,trifluoromethoxy, nitro, cyano or N(R^(E))₂;

R³ is selected from the group consisting of aryl, arC₁₋₆alkyl andheteroaryl; wherein the aryl, arC₁₋₆alkyl or heteroaryl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^(E))₂;

n is an integer from 0 to 2;

R⁴ is selected from the group consisting of hydroxy, C₁₋₄alkyl andhydroxy substituted C₁₋₄alkyl;

m is an integer from 0 to 1;

L¹ is selected from the group consisting of C₁₋₆alkyl and C₃₋₆alkenyl;wherein the double bond of the C₃₋₆alkenyl group is at least one carbonatom removed from the attachment point to the N atom; and wherein theC₁₋₆alkyl or C₃₋₆alkenyl group is optionally substituted with one to twosubstituents independently selected from hydroxy, fluoro, C₁₋₆alkyl,fluorinated C₁₋₆alkyl or C₁₋₆alkoxy;

is selected from the group consisting of cycloalkyl, partiallyunsaturated carbocyclyl, aryl, heteroaryl and heterocycloalkyl;

p is an integer from 0 to 5;

R⁵ is selected from the group consisting of hydroxy, carboxy, halogen,C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, NR¹R², trifluoromethyl,trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO—NR¹R², —SO₂—NR¹R² and—C(O)—NR¹R²;

q is an integer from 0 to 1;

R⁶ is selected from the group consisting of -(L²)₀₋₁-R⁷;

L² is selected from the group consisting of —C₁₋₆alkyl-, —C₂₋₄alkenyl-,-C₂₋₆alkynyl-, —O—, —S—, —NH—, —N(C₁₋₄alkyl)-, —C₁₋₆alkyl-O—,—C₁₋₆alkyl-S—, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —O—C₂₋₆alkyl-O—,—S—C₂₋₆alkyl-S—, —SO₂—, —SO₂NH—, —SO₂N(C₁₋₄alkyl)-, —NH—SO₂—,—N(C₁₋₄alkyl)-SO₂—, —C(O)—O— and —O—C(O)—;

R⁷ is selected from the group consisting of aryl, partially unsaturatedcarbocyclyl, cycloalkyl, heteroaryl and heterocycloalkyl; wherein thearyl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl orheterocycloalkyl group is optionally substituted with one or moresubstituents independently selected from hydroxy, carboxy, halogen,C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, N(R^(E))₂, trifluoromethyl,trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO₂—N(R^(E))₂ and—C(O)—N(R^(E))₂;

and pharmaceutically acceptable salts thereof.

In an embodiment of the present invention are compounds of the formula(E)

wherein R³, n, R⁴, and Y are as herein defined, or a pharmaceuticallyacceptable salt thereof. The compounds of formula (E) are useful asintermediates in the preparation of compounds of formula (I).

In an embodiment of the present invention are compounds of formula (E)wherein R³ is selected from the group consisting of aryl, arC₁₋₆alkyland heteroaryl; wherein the aryl, arC₁₋₆alkyl or heteroaryl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^(E))₂; whereineach R^(E) is independently selected from hydrogen or C₁₋₄alkyl;

n is an integer from 0 to 2;

R⁴ is selected from the group consisting of hydroxy, C₁₋₄alkyl andhydroxy substituted C₁₋₄alkyl;

Y is selected from the group consisting of hydrogen, C₁₋₄alkyl,t-butoxycarbonyl and

m is an integer from 0 to 1;

L¹ is selected from the group consisting of C₁₋₆alkyl and C₃₋₆alkenyl;wherein the double bond of the C₃₋₆alkenyl group is at least one carbonatom removed from the attachment point to the N atom; and wherein theC₁₋₆alkyl or C₃₋₆alkenyl group is optionally substituted with one to twosubstituents independently selected from hydroxy, fluoro, C₁₋₆alkyl,fluorinated C₁₋₆alkyl or C₁₋₆alkoxy;

is selected from the group consisting of cycloalkyl, partiallyunsaturated carbocyclyl, aryl, heteroaryl and heterocycloalkyl;

p is an integer from 0 to 5;

R⁵ is selected from the group consisting of hydroxy, carboxy, halogen,C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, NR¹R², trifluoromethyl,trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO—NR¹R², —SO₂—NR¹R² and—C(O)—NR¹R²;

q is an integer from 0 to 1;

R⁶ is selected from the group consisting of -(L²)₀₋₁-R⁷;

L² is selected from the group consisting of —C₁₋₆alkyl-, —C₂₋₄alkenyl-,—C₂₋₆alkynyl-, —O—, —S—, —NH—, —N(C₁₋₄alkyl)-, —C₁₋₆alkyl-O—,—C₁₋₆alkyl-S—, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-, —O—C₂₋₆alkyl-O—,—S—C₂₋₆alkyl-S—, —SO₂—, —SO₂NH—, —SO₂N(C₁₋₄alkyl)-, —NH—SO₂—,—N(C₁₋₄alkyl)-SO₂—, —C(O)—O— and —O—C(O)—;

R⁷ is selected from the group consisting of aryl, partially unsaturatedcarbocyclyl, cycloalkyl, heteroaryl and heterocycloalkyl; wherein thearyl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl orheterocycloalkyl group is optionally substituted with one or moresubstituents independently selected from hydroxy, carboxy, halogen,C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, N(R^(E))₂, trifluoromethyl,trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO₂—N(R^(E))₂ and—C(O)—N(R^(E))₂;

and pharmaceutically acceptable salts thereof.

In an embodiment of the present invention are compounds of the formula(Ia)

wherein X, R³, n, R⁴, m, L¹,

p, R⁵, q and R⁶ are as herein defined, or a pharmaceutically acceptablesalt thereof. The compounds of formula (I) are useful in the treatmentof disorders mediated by the ORL-1 receptor.

In an embodiment of the present invention is a compound of formula (I)wherein the binding of the compound to the ORL-1 receptor is 10 foldgreater than the binding of the compound to the μ opioid (OP-3)receptor. In another embodiment of the present invention is a compoundof formula (I) wherein the binding of the compound to the ORL-1 receptoris 100 fold greater, preferably 500 fold greater, more preferably 1000fold greater, than the binding of the compound to the μ opioid (OP-3)receptor.

In an embodiment of the present invention is a compound of formula (I)wherein the compound's measured IC₅₀ to the ORL-1 receptor is less thanor equal to about 100 nM, preferably less than or equal to about 50 nM.In another embodiment of the present invention is a compound of formula(I) wherein the compound's measured Ki to the ORL-1 receptor is lessthan or equal to about 100 nM, preferably less than or equal to about 50nM.

In an embodiment of the present invention R⁰ is

In another embodiment of the present invention, R⁰ is

In yet another embodiment of the present invention, R⁰ is

Preferably, R⁰ is selected from the group consisting of

and

More preferably, R⁰ is

In yet another embodiment of the present invention, R⁰ is

Preferably, R⁰ is

In an embodiment of the present invention, the hydroxy group on the

group is present in the R stereo-configuration. In another embodiment ofthe present invention, the hydroxy group on the

group is present in the S stereo-configuration.

In an embodiment of the present invention R^(A) and R^(B) are eachindependently selected from hydrogen, methyl and ethyl, preferably R^(A)and R^(B) are each hydrogen. In another embodiment of the presentinvention R^(C) and R^(D) are each independently selected from hydrogenand C₁₋₄alkyl, preferably R^(C) and R^(D) are each hydrogen. In yetanother embodiment of the present invention R^(E) is selected from thegroup consisting of hydrogen, methyl and ethyl, preferably R^(E) ishydrogen.

In an embodiment of the present invention X is selected from the groupconsisting of —NR¹R², —C(O)—NR¹R², —NR¹—C(O)—R², —OR¹, —SR¹, —SO—R¹,—SO₂—R¹, —S—(C₂₋₄alkyl)-NR¹R², —SO—(C₁₋₄alkyl)-NR¹R²,—SO₂—(C₁₋₄alkyl)-NR¹R² wherein the alkyl portion of the—S—(C₂₋₄alkyl)-NR¹R², —S—(C₁₋₄alkyl)-NR¹—C(O)O—C(CH₃)₃,—SO—(C₁₋₄alkyl)-NR¹R² or —SO₂—(C₁₋₄alkyl)-NR¹R² group is optionallysubstituted with one to two substituents independently selected fromC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₁₋₄alkoxycarbonyl or carboxy. Preferably,X is selected from the group consisting of —NR¹R², —OR¹, —SR¹,—S—(C₂₋₄alkyl)—NR¹—C(O)O—C(CH₃)₃, —S—(C₂₋₄alkyl)-NR¹R² wherein the alkylportion of the —S—(C₂₋₄alkyl)-NR¹R² or —S—(C₂₋₄alkyl)-NR¹—C(O)O—C(CH₃)₃group is optionally substituted with a carboxy or C₁₋₄alkoxycarbonylgroup. More preferably, X is selected from the group consisting of—NR¹R², —OR¹, —SR¹, —S—CH₂CH(CO₂H)—NH—C(O)—CH₃ and—S—CH₂CH(CO₂H)—NH—C(O)O—C(CH₃)₃. More preferably still, X is selectedfrom the group consisting of —NR¹R², —SR¹ and—S—CH₂CH(CO₂H)—NH—C(O)—CH₃.

In an embodiment of the present invention R¹ is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, aryl,arC₁₋₄alkyl, arC₁₋₄alkyloxy, heteroaryl, heteroaryl-alkyl,heterocycloalkyl, heterocycloalkyl-alkyl, cycloalkyl-alkyl,C(O)—C₁₋₄alkyl and —C(O)-heteroaryl; wherein the C₁₋₄alkyl, aryl,arC₁₋₄alkyl, heteroaryl, heterocycloalkyl or cycloalkyl group, whetheralone or part of a substituent group, is optionally substituted with oneto three substituents independently selected from halogen, hydroxy,carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, N(R^(E))₂,N(R^(E))₂—C₁₋₄alkyl, N(R^(E))—C(O)OC(CH₃)₃, nitro, trifluoromethyl,trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl,1-phenyl-pyrazol-2-yl-aminosulfonyl or C₁₋₄alkylthio. Preferably, In anembodiment of the present invention R¹ is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, aryl, arC₁₋₄alkyl,arC₁₋₄alkyloxy, heteroaryl, heteroaryl-alkyl, heterocycloalkyl,heterocycloalkyl-alkyl, cycloalkyl-alkyl, C(O)—C₁₋₄alkyl and—C(O)-heteroaryl; wherein the C₁₋₄alkyl, aryl, arC₁₋₄alkyl, heteroaryl,heterocycloalkyl or cycloalkyl group, whether alone or part of asubstituent group, is optionally substituted with one to threesubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, N(R^(E))₂,N(R^(E))₂—C₁₋₄alkyl, N(R^(E))—C(O)OC(CH₃)₃, nitro, trifluoromethyl,trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl,1-phenyl-pyrazol-2-yl-aminosulfonyl or C₁₋₄alkylthio.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, C₁₋₄alkyl, arC₁₋₄alkyl, C₁₋₄alkoxycarbonyland C(O)—C₁₋₄alkyl; wherein the C₁₋₄alkyl, arC₁₋₄alkyl or aryl group,whether alone or part of a substituent group, is optionally substitutedwith one to two substituents independently selected from carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, N(R^(E))₂,N(R^(E))₂—C₁₋₄alkyl or N(R^(E))—C(O)OC(CH₃)₃. Preferably, R¹ is selectedfrom the group consisting of hydrogen, C₁₋₄alkyl, arC₁₋₄alkyl andC(O)—C₁₋₄alkyl; wherein the C₁₋₄alkyl, arC₁₋₄alkyl or aryl group,whether alone or part of a substituent group, is optionally substitutedwith one to two substituents independently selected from carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, N(R^(E))₂,N(R^(E))₂—C₁₋₄alkyl or N(R^(E))—C(O)OC(CH₃)₃.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl,amino-n-propyl, dimethylaminoethyl, benzyl, phenylethyl,4-methyl-benzyl,

2-(3,4-dimethoxy-phenyl)ethyl, 3-methylphenyl,2-amino-2-methoxycarbonyl-ethyl, ethoxy-carbonyl-methyl,t-butoxycarbonyl, and

Preferably, R¹ is selected from the group consisting of hydrogen,methyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl,4-methyl-benzyl,

2-(3,4-dimethoxy-phenyl)ethyl, 3-methylphenyl,2-amino-2-methoxycarbonyl-ethyl and

In another embodiment of the present invention, R¹ is selected from thegroup consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl,dimethylaminoethyl, benzyl, phenylethyl,

3-methyl-phenyl, 2-(3,4-dimethoxyphenyl)-ethyl, ethoxy-carbonyl-methyl,dimethylamino-ethyl and 2-amino-2-methoxycarbonyl-ethyl. Preferably, R¹is selected from the group consisting of hydrogen, methyl, ethyl,n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl,

3-methyl-phenyl and 2-amino-2-methoxycarbonyl-ethyl.

In yet another embodiment of the present invention, R¹ is selected fromthe group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl,t-butyl, dimethylaminoethyl, benzyl, phenylethyl,2-(3,4-dimethoxyphenyl)-ethyl, dimethylamino-ethyl,ethoxy-carbonyl-methyl,

Preferably, R¹ is selected from the group consisting of hydrogen,methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl,

In another embodiment of the present invention R¹ is selected from thegroup consisting of hydrogen, t-butoxycarbonyl,2-(3,4-dimethoxyphenyl)-ethyl, 1-(3,4-dimethoxyphenyl)-n-ethyl andamino-n-propyl. In yet another embodiment of the present invention R¹ isselected from the group consisting of hydrogen, t-butoxycarbonyl andamino-n-propyl.

In an embodiment of the present invention R² is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, cycloalkyl,cycloalkyl-C₁₋₄alkyl, aryl, arC₁₋₄alkyl, arC₁₋₄alkyloxy, partiallyunsaturated carbocyclyl, particularly unsaturated carbocyclyl-C₁₋₄alkyl,heteroaryl, heteroaryl-C₁₋₄alkyl, heterocycloalkyl,heterocycloalkyl-C₁₋₄alkyl, —C(O)—C₁₋₄alkyl, —C(O)-aryl,—C(O)-arC₁₋₄alkyl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl,—C(O)O-cycloalkyl and —C(OO)—C₁₋₄alkyl; wherein the C₁₋₄alkyl, aryl,arC₁₋₄alkyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl or cycloalkyl group, whether alone or part of asubstituent group, is optionally substituted with one to threesubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, N(R^(E))₂,N(R^(E))₂—C₁₋₄alkyl, (CH₃)₃COC(O)—N(R^(E))—C₁₋₄-alkyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl,cycloalkyl, 1-phenyl substituted heteroaryl-aminosulfonyl,—C(O)—C₁₋₄alkyl or C₁₋₄alkylthio. Preferably, R² is selected from thegroup consisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy,cycloalkyl-C₁₋₄alkyl, aryl, arC₁₋₄alkyl, arC₁₋₄alkyloxy, partiallyunsaturated carbocyclyl, heteroaryl, heteroaryl-C₁₋₄alkyl,heterocycloalkyl, heterocycloalkyl-C₁₋₄alkyl, —C(O)—C₁₋₄alkyl,—C(O)-aryl, —C(O)-arC₁₋₄alkyl, —C(O)-heteroaryl and—C(O)-heterocycloalkyl; wherein the C₁₋₄alkyl, aryl, arC₁₋₄alkyl,partially unsaturated carbocyclyl, heteroaryl, heterocycloalkyl orcycloalkyl group, whether alone or part of a substituent group, isoptionally substituted with one to three substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, N(R^(E))₂, N(R^(E))₂—C₁₋₄alkyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl,cycloalkyl, 1-phenyl substituted heteroaryl-aminosulfonyl,—C(O)—C₁₋₄alkyl or C₁₋₄alkylthio.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, cycloalkyl, aryl,arC₁₋₄alkyl, arC₁₋₄alkyloxy, partially unsaturated carbocyclyl,partially unsaturated carbocyclyl-C₁₋₄alkyl, heteroaryl,heteroaryl-C₁₋₄alkyl, heterocycloalkyl, heterocycloalkyl-C₁₋₄alkyl,cycloalkyl-C₁₋₄alkyl, —C(O)arC₁₋₄alkyl, —C(O)-heteroaryl,—C(OO)-cycloalkyl and —C(O)O—C₁₋₄alkyl; wherein the C₁₋₄alkyl, aryl,arC₁₋₄alkyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl or cycloalkyl group, whether alone or part of asubstituent group, is optionally substituted with one to threesubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, N(R^(E))₂,N(R^(E))₂—C₁₋₄alkyl, alkyl, nitro, trifluoromethyl, trifluoromethoxy,phenyl, phenoxy, heteroaryl, cycloalkyl,1-phenyl-pyrazol-2-yl-aminosulfonyl or C₁₋₄alkylthio. Preferably, R² isselected from the group consisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy,aryl, arC₁₋₄alkyl, arC₁₋₄alkyloxy, partially unsaturated carbocyclyl,heteroaryl, heteroaryl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl,cycloalkyl-alkyl and —C(O)-heteroaryl; wherein the C₁₋₄alkyl, aryl,arC₁₋₄alkyl, partially unsaturated carbocyclyl, heteroaryl,heterocycloalkyl or cycloalkyl group, whether alone or part of asubstituent group, is optionally substituted with one to threesubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, N(R^(E))₂,N(R^(E))₂—C₁₋₄alkyl, nitro, trifluoromethyl, trifluoromethoxy, phenyl,phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl orC₁₋₄alkylthio.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, methyl, methoxy, ethyl, carboxy-methyl,methoxycarbonylmethyl, 2,2,2-trifluoroethyl, ethoxy, dimethylaminoethyl,t-butoxycarbonylamino-ethyl, n-butyl, t-butyl, n-propyl,3-hydroxy-n-propyl, 3-methoxy-n-propyl, methylamino-n-propyl,dimethylamino-n-propyl, di(n-butyl)amino-n-propyl,t-butoxycarbonylamino-n-propyl, 3-phenyl-n-propyl,3-(2-pyridyl)-n-propyl, t-butoxycarbonyl, cyclopropyl, phenyl,4-fluorophenyl, 4-methylphenyl, 3,4-dimethoxyphenyl, 2-aminophenyl,4-biphenyl, 2-ethoxyphenyl,4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-cyclohexylphenyl,4-(aminoethyl)phenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl,—CH(CH₃)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl,2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl,4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl), 3-iodobenzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl,3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl,4-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 2,3-dimethoxybenzyl,2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl,2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl,2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl,3,4-difluorobenzyl, 3,5-di(trifluoromethyl)benzyl,4-(dimethylamino)benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl,2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl,2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxyphenyl)ethyl,3-(4-morpholinyl)-n-propyl, 2-(4-morpholinyl)ethyl,2-(4-imidazolyl)ethyl, 1-adamantanyl, 1-adamantanyl-methyl,(2,5-dimethoxy-2,5-dihydro-fur-2-yl)methyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl,2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl), 2-(4,6-dimethyl-pyridyl),2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl),6-methylthio-2-pyridyl-carbonyl, thienyl-methyl, 2-thienylethyl,4-pyridinyl, 1-naphthyl, 1-naphthyl-methyl,1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl,1-phenyl-2-(t-butoxycarbonyl)ethyl, —C(O)—C(OCH₃)(CF₃)-phenyl,—C(O)O-(2-isopropyl-5-methyl-cyclohexyl),1-(4-ethoxycarbonyl-piperidinyl), 2-(3H-imidazol-4-yl)ethyl,2-(1,2,3,4-tetrahydro-isoquinolinyl), 2-furyl-methyl,

2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl,2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl, 2-(2-pyridyl)-ethyl,2-(6-fluoro-2-indolyl)ethyl and 2-phenyl-cyclopropyl. Preferably, R² isselected from the group consisting of hydrogen, methyl, methoxy, ethyl,carboxy-methyl, ethoxycarbonylmethyl, 2,2,2,-trifluoroethyl, ethoxy,dimethylaminoethyl, n-butyl, t-butyl, n-propyl,di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl,phenyl, 4-biphenyl, 2-ethoxyphenyl,4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-cyclohexylphenyl,4-(aminoethyl)phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl,2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl,4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl), 3-iodobenzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl,3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl,4-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 2,3-dimethoxybenzyl,2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl,2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl,2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl,3,4-difluorobenzyl, 3,5-di(trifluoromethyl)benzyl,4-(dimethylamino)benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl,2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl,2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxyphenyl)ethyl,3-(4-morpholinyl)-n-propyl, 2-(4-morpholinyl)ethyl,2-(4-imidazolyl)ethyl, 1-adamantanyl, 1-adamantanyl-methyl,(2,5-dimethoxy-2,5-dihydro-fur-2-yl)methyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl,2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl), 2-(4,6-dimethyl-pyridyl),2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl),6-methylthio-2-pyridyl-carbonyl, 2-thienylethyl, 1-naphthyl,1-naphthyl-methyl, 1-(3,4-methylenedioxyphenyl)methyl,2-(3,4-methylenedioxyphenyl)ethyl, 1-phenyl-2-(t-butoxycarbonyl)ethyl,2-(1,2,3,4-tetrahydro-isoquinolinyl), 2-furyl-methyl,

2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl,2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl, 2-(2-pyridyl)-ethyl,2-(6-fluoro-2-indolyl)ethyl and 2-phenyl-cyclopropyl.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl,2,2,2-trifluoroethyl, ethoxy, dimethylaminoethyl, n-butyl, t-butyl,n-propyl, di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl,3-(2-pyridyl)-n-propyl, cyclopropyl, phenyl, 4-fluorophenyl,4-methylphenyl, 2-aminophenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl,3,4-dimethoxyphenyl, 4-biphenyl, 2-ethoxyphenyl,4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-(aminoethyl)-phenyl,benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl,3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 3-iodobenzyl, 2-fluorobenzyl,3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl,3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl,4-trifluoromethoxybenzyl, 4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl,2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl,2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl,2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl,3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl, 2-phenylethyl,2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl,2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 3-(4-morpholinyl)-n-propyl,2-(4-morpholinyl)ethyl, 2-(4-imidazolyl)ethyl, adamantanyl,1-adamantanyl-methyl, 2-(2,5-dimethoxy-2,5-dihydro-furyl)methyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl,4-pyridyl-methyl, 2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl),2-(4,6-dimethyl-pyridyl), 2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl),thienylmethyl, 2-thienylethyl, 1-naphthyl, 1-naphthyl-methyl,1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl,2-furyl-methyl,

2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl,2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl and2-(6-fluoro-2-indolyl)-ethyl. Preferably still, R² is selected from thegroup consisting of hydrogen, methyl, methoxy, ethyl,ethoxycarbonyl-methyl, 2,2,2-trifluoroethyl, ethoxy, dimethylaminoethyl,n-butyl, t-butyl, n-propyl, di(n-butyl)amino-n-propyl,3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl, phenyl, 4-biphenyl,2-ethoxyphenyl, 4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl,4-(aminoethyl)-phenyl, benzyl, benzyloxy, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl,4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl,3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl,3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl,4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl,3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl,3,5-di(trifluoromethyl)-benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl,2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl,2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl,3-(4-morpholinyl)-n-propyl, 2-(4-morpholinyl)ethyl,2-(4-imidazolyl)ethyl, adamantanyl, 1-adamantanyl-methyl,2-(2,5-dimethoxy-2,5-dihydro-furyl)methyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl, 4-pyridyl-methyl,2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl), 2-(4,6-dimethyl-pyridyl),2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl), 2-thienylethyl, 1-naphthyl,1-naphthyl-methyl, 1-(3,4-methylenedioxyphenyl)methyl,2-(3,4-methylenedioxyphenyl)ethyl, 2-furyl-methyl,

2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl,2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl and2-(6-fluoro-2-indolyl)-ethyl.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl,ethoxy, dimethylaminoethyl, n-butyl, n-propyl,di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl,cyclopropyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 2-aminophenyl,3,4-dimethoxyphenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl, 4-biphenyl,2-ethoxyphenyl, 4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl,4-(aminoethyl)-phenyl, benzyl, benzyloxy, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl,4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl,3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl,3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 3-nitrobenzyl,4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl,3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl,2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl,2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 3-(4-morpholinyl)-n-propyl,2-(4-morpholinyl)ethyl, 2-(4-imidazolyl)ethyl, 1-adamantanyl,1-adamantanyl-methyl, 2-(2,5-dimethoxy-2,5-dihydro-furyl)methyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl,4-pyridyl-methyl, 2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl),2-(4,6-dimethyl-pyridyl), 2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl),thienylmethyl, 2-thienylethyl, 1-naphthyl, 1-naphthyl-methyl,1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl,2-furyl-methyl,

2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl,2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl. Preferably, R² isselected from the group consisting of hydrogen, methyl, methoxy, ethyl,ethoxycarbonyl-methyl, ethoxy, dimethylaminoethyl, n-butyl, n-propyl,di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl,4-biphenyl, 2-ethoxyphenyl,4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-(aminoethyl)-phenyl,benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl,3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 3-iodobenzyl, 2-fluorobenzyl,3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl,3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl,4-trifluoromethoxybenzyl, 4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl,2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl,2,5-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl,3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl,3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl,2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl,2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 3-(4-morpholinyl)-n-propyl,2-(4-morpholinyl)ethyl, 2-(4-imidazolyl)ethyl, 1-adamantanyl,1-adamantanyl-methyl, 2-(2,5-dimethoxy-2,5-dihydro-furyl)methyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl-methyl, 3-pyridyl-methyl,4-pyridyl-methyl, 2-(3,4-dimethyl-pyridyl), 2-(5-bromopyridyl),2-(4,6-dimethyl-pyridyl), 2-(5-methyl-pyridyl), 3-(6-methoxy-pyridyl),2-thienylethyl, 1-naphthyl, 1-naphthyl-methyl,1-(3,4-methylenedioxyphenyl)methyl, 2-(3,4-methylenedioxyphenyl)ethyl,2-furyl-methyl,

2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl,2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl.

In an embodiment of the present invention R² is selected from the groupconsisting of hydrogen, methyl, n-butyl, 3-hydroxy-n-propyl,3-methoxy-n-propyl, methylamino-n-propyl, dimethylamino-n-propyl,t-butoxycarbonylamino-n-propyl,N-methyl-N-t-butoxycarbonyl-amino-n-ethyl, 3-nitrobenzyl,4-methoxycarbonyl-benzyl, —CH(CH₃)-phenyl, 4-pyridinyl,1-(4-ethoxycarbonyl-piperidinyl) and 2-(3H-imidazol-4-yl)-ethyl.

Preferably, R² is selected from the group consisting of hydrogen,methyl, n-butyl, 3-hydroxy-n-propyl, 3-methoxy-n-propyl,methylamino-n-propyl, dimethylamino-n-propyl,N-methyl-N-t-butoxycarbonyl-amino-n-ethyl, 3-nitrobenzyl,4-methoxycarbonyl-benzyl, —CH(CH₃)-phenyl, 4-pyridinyl and2-(3H-imidazol-4-yl)-ethyl.

In an embodiment of the present invention, when R¹ and R² are both boundto the same nitrogen atom, R¹ and R² are taken together with thenitrogen atom to which they are bound to form a heteroaryl orheterocycloalkyl group; wherein the heteroaryl or heterocycloalkyl isoptionally substituted with one to three substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, hydroxy substitutedC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, trifluoromethyl,trifluoromethoxy, nitro, cyano, N(R^(E))₂, phenyl, arC₁₋₄alkyl,heterocycloalkyl, di(C₁₋₄alkyl)amino-carbonyl, C₁₋₄alkoxycarbonylaminoor phenylamino-C₁₋₄alkyl; wherein the phenyl or arC₁₋₄alkyl substituenton the heteroaryl or heterocycloalkyl group is optionally substitutedwith one or two substituents independently selected from halogen,hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl,trifluoromethoxy, nitro, cyano, N(R^(E))₂ or substituted phenyl; whereinthe substituents on the phenyl are one to three independently selectedfrom halogen. Preferably, when R¹ and R² are both bound to the samenitrogen atom, R¹ and R² are taken together with the nitrogen atom towhich they are bound to form a heteroaryl or heterocycloalkyl group;wherein the heteroaryl or heterocycloalkyl is optionally substitutedwith one to three substituents independently selected from halogen,hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,trifluoromethyl, trifluoromethoxy, nitro, cyano, N(R^(E))₂, phenyl,arC₁₋₄alkyl, heterocycloalkyl, di(C₁₋₄alkyl)amino-carbonyl, orphenylamino-C₁₋₄alkyl; wherein the phenyl or arC₁₋₄alkyl substituent onthe heteroaryl or heterocycloalkyl group is optionally substituted withone or two substituents independently selected from halogen, hydroxy,carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy,nitro, cyano, N(R^(E))₂ or substituted phenyl; wherein the substituentson the phenyl are one to three independently selected from halogen.

In an embodiment of the present invention, when R¹ and R² are both boundto the same nitrogen atom, R¹ and R² are taken together with thenitrogen atom to which they are bound to form a group selected fromheterocycloalkyl and heteroaryl; wherein the heteroaryl orheterocycloalkyl is optionally substituted with one or more substituentsindependently selected from hydroxy, carboxy, C₁₋₄alkyl, hydroxysubstituted C₁₋₄alkyl, C₁₋₄alkoxy, phenyl, arC₁₋₄alkyl,heterocycloalkyl, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, di(C₁₋₄alkyl)amino-carbonyl, t-butoxycarbonyl,t-butoxycarbonylamino or phenylamino-C₁₋₄alkyl; wherein the phenyl orarC₁₋₄alkyl substituent is optionally substituted with one or twosubstituents independently selected from chloro, trifluoromethyl orchlorophenyl. Preferably, when R¹ and R² are both bound to the samenitrogen atom, R¹ and R² are taken together with the nitrogen atom towhich they are bound to form a group selected from heterocycloalkyl andheteroaryl; wherein the heteroaryl or heterocycloalkyl is optionallysubstituted with one or more substituents independently selected fromC₁₋₄alkyl, C₁₋₄alkoxy, phenyl, arC₁₋₄alkyl, heterocycloalkyl,C₁₋₄alkoxycarbonyl, di(C₁₋₄alkyl)amino-carbonyl orphenylamino-C₁₋₄alkyl; wherein the phenyl or arC₁₋₄alkyl substituent isoptionally substituted with one or two substituents independentlyselected from trifluoromethyl or chlorophenyl.

In an embodiment of the present invention, when R¹ and R² are both boundto the same nitrogen atom, R¹ and R² are taken together with thenitrogen atom to which they are bound to form a group selected from1-morpholinyl, 1-(4-(3-trifluoromethyl-phenyl)-piperazinyl),1-(4-piperidinyl-piperidinyl), 1-(4-pyrrolidinyl-piperidinyl),1-(4-phenyl-piperidinyl), 1-(3-hydroxy-piperidinyl),1-(4-hydroxy-piperidinyl), 1-(3-hydroxymethyl-piperidinyl),1-(3,5-dimethyl-piperidinyl), 1-(4-dimethylamino-piperidinyl),1-(4-(3,4-methylenedioxyphenylmethyl)-piperazinyl),1-(3-(diethylaminocarbonyl)-piperidinyl),1-(4-t-butoxycarbonylamino-piperidinyl), 1-(2,3-dihydro-1H-pyrrolyl),1-(4-[(4-chlorophenyl)-phenyl-methyl]-piperazinyl),2-(1,2,3,4-tetrahydro-isoquinolinyl),1-(4-t-butoxycarbonyl-piperazinyl),2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl),4-(2,6-dimethyl-morpholinyl), 1-(4-benzyl-piperazinyl), 1-pyrrolidinyl,1-(2,3,-dihydro-pyrrolidinyl), 1-(3-hydroxy-pyrrolidinyl),1-(3-(S)-hydroxy-pyrrolidinyl), 1-piperidinyl,1-(3-ethoxycarbonyl-piperidinyl), 1-(4-ethoxycarbonyl-piperidinyl),1-imidazolyl, 1-(2-(phenylamino-methyl)-N-pyrrolidinyl),1-(3-(R)-dimethylamino-pyrrolidinyl), 1-(3-(R)-hydroxy-pyrrolidinyl),1-(3,4-dihydroxy-2,5-bis-hydrooxymethyl-pyrrolidinyl),1-(3-(R)-t-butoxycarbonylamino-pyrrolidinyl),1-(3-(S)-ethylamino-pyrrolidinyl), 1-(3-(R)-amino-pyrrolidinyl),1-(3-(S)-amino-pyrrolidinyl), 1-(3-(R)-methylamino-pyrrolidinyl),1-(3-(S)-methylamino-pyrrolidinyl),1-(3-(N-methyl-N-t-butoxycarbonyl-amino)-pyrrolidinyl) or1-(2-(3,5-dichlorophenyl)-3-methyl-5-carboxy-1,2,4-triazolyl).Preferably, when R¹ and R² are both bound to the same nitrogen atom, R¹and R² are taken together with the nitrogen atom to which they are boundto form a group selected from1-(4-(3-trifluoromethyl-phenyl)-piperazinyl),1-(4-piperidinyl-piperidinyl),1-(4-(3,4-methylenedioxyphenylmethyl)-piperazinyl),1-(3-(diethylaminocarbonyl)-piperidinyl), 1-(2,3-dihydro-1H-pyrrolyl),1-(4-[(4-chlorophenyl)-phenyl-methyl]-piperazinyl),2-(1,2,3,4-tetrahydro-isoquinolinyl),1-(4-t-butoxycarbonyl-piperazinyl),2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl),4-(2,6-dimethyl-morpholinyl), 1-(4-benzyl-piperazinyl), 1-pyrrolidinyl,1-piperidinyl, 1-(4-ethoxycarbonyl-piperidinyl), 1-imidazolyl and1-(2-(phenylamino-methyl)-N-pyrrolidinyl).

In an embodiment of the present invention, when R¹ and R² are both boundto the same nitrogen atom, R¹ and R² are taken together with thenitrogen atom to which they are bound to form a group selected from1-(4-(3-trifluoromethyl-phenyl)-piperazinyl), 1-(4-phenyl-piperidinyl),1-(4-piperidinyl-piperidinyl),1-(4-(3,4-methylenedioxyphenyl-methyl)-piperazinyl),1-(3-(diethylaminocarbonyl)-piperidinyl),1-(4-[(4-chlorophenyl)-phenylmethyl]-piperiazinyl),2-(1,2,3,4-tetrahydro-isoquinolinyl),1-(4-t-butoxycarbonyl-piperazinyl),2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl),4-(2,6-dimethyl-morpholinyl), 1-(4-benzyl-piperazinyl), 1-morpholinyl,1-pyrrolidinyl, 1-(2,3-dihydro-pyrrolidinyl), 1-piperidinyl,1-(3,5-dimethyl-piperidinyl), 1-(3-hydroxymethyl-piperidinyl),1-(3-ethoxycarbonyl-piperidinyl), 1-(4-(ethoxycarbonyl)-piperidinyl),1-imidazolyl and 1-(2-(phenylamino-methyl)-N-pyrrolidinyl). Preferably,when R¹ and R² are both bound to the same nitrogen atom, R¹ and R² aretaken together with the nitrogen atom to which they are bound to form agroup selected from 1-(4-(3-trifluoromethyl-phenyl)-piperazinyl),1-(4-piperidinyl-piperidinyl),1-(4-(3,4-methylenedioxyphenyl-methyl)-piperazinyl),1-(3-(diethylaminocarbonyl)-piperidinyl),1-(4-[(4-chlorophenyl)-phenylmethyl]-piperiazinyl),2-(1,2,3,4-tetrahydro-isoquinolinyl),1-(4-t-butoxycarbonyl-piperazinyl),2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl),4-(2,6-dimethyl-morpholinyl), 1-(4-benzyl-piperazinyl), 1-pyrrolidinyl,1-piperidinyl, 1-(4-(ethoxycarbonyl)-piperidinyl), 1-imidazolyl and1-(2-(phenylamino-methyl)-N-pyrrolidinyl).

In an embodiment of the present invention, when R¹ and R² are both boundto the same nitrogen atom, R¹ and R² are taken together with thenitrogen atom to which they are bound to form a group selected from1-(4-(3-trifluoromethyl-phenyl)-piperazinyl), 1-(4-phenyl-piperidinyl),1-(4-piperidinyl-piperidinyl),1-(4-(3,4-methylenedioxyphenyl-methyl)-piperazinyl),1-(3-(diethylaminocarbonyl)-piperidinyl),1-(4-[(4-chlorophenyl)-phenylmethyl]-piperiazinyl),2-(1,2,3,4-tetrahydro-isoquinolinyl),1-(4-t-butoxycarbonyl-piperazinyl),2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl),4-(2,6-dimethyl-morpholinyl), 1-(4-benzyl-piperazinyl),1-(3,5-dimethyl-piperidinyl), 1-(3-hydroxymethyl-piperidinyl),1-(3-ethoxycarbonyl-piperidinyl), 1-(4-(ethoxycarbonyl)-piperidinyl),1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, 1-imidazolyl,1-(2,3-dihydro-pyrrolidinyl), and1-(2-(phenylamino-methyl)-N-pyrrolidinyl). Preferably, when R¹ and R²are both bound to the same nitrogen atom, R¹ and R² are taken togetherwith the nitrogen atom to which they are bound to form a group selectedfrom 1-(4-(3-trifluoromethyl-phenyl)-piperazinyl),1-(4-piperidinyl-piperidinyl),1-(4-(3,4-methylenedioxyphenyl-methyl)-piperazinyl),1-(3-(diethylaminocarbonyl)-piperidinyl),1-(4-[(4-chlorophenyl)-phenylmethyl]-piperiazinyl),2-(1,2,3,4-tetrahydro-isoquinolinyl),1-(4-t-butoxycarbonyl-piperazinyl),2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl),4-(2,6-dimethyl-morpholinyl), 1-(4-benzyl-piperazinyl),1-(4-(ethoxycarbonyl)-piperidinyl), 1-piperidinyl, 1-imidazolyl and1-(2-(phenylamino-methyl)-N-pyrrolidinyl).

In an embodiment of the present invention, when R¹ and R² are both boundto the same nitrogen atom, R¹ and R² are taken together with thenitrogen atom to which they are bound to form a group selected from2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl),1-(4-[(4-chlorophenyl)-phenylmethyl]-piperazinyl), 1-pyrrolidinyl,1-(3-hydroxy-pyrrolidinyl), 1-(3-(R)-hydroxy-pyrrolidinyl),1-(4-hydroxy-piperidinyl), 1-(3-(R)-dimethylamino-pyrrolidinyl),1-(4-t-butoxycarbonylamino-pyrrolidinyl),1-(3-(R)-t-butoxycarbonylamino-pyrrolidinyl),1-(3-(R)-amino-pyrrolidinyl), 1-(3-(S)-amino-pyrrolidinyl),1-(3-(R)-methylamino-pyrrolidinyl), 1-(3-(S)-ethylamino-pyrrolidinyl),1-(4-dimethylamino-pyrrolidinyl),1-(3-(N-methyl-N-t-butoxycarbonyl-amino-pyrrolidinyl) or1-(2-(3,5-dichlorophenyl)-3-methyl-5-carboxy-1,2,4-triazolyl).

Preferably, when R¹ and R² are both bound to the same nitrogen atom, R¹and R² are taken together with the nitrogen atom to which they are boundto form a group selected from2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl),1-(4-[(4-chlorophenyl)-phenyl-methyl]-piperazinyl), 1-pyrrolidinyl,1-(3-hydroxy-pyrrolidinyl), 1-(3-(R)-hydroxy-pyrrolidinyl),1-(4-hydroxy-piperidinyl), 1-(3-(R)-dimethylamino-pyrrolidinyl),1-(4-t-butoxycarbonylamino-pyrrolidinyl),1-(3-(R)-t-butoxycarbonylamino-pyrrolidinyl),1-(3-(R)-amino-pyrrolidinyl), 1-(3-(S)-amino-pyrrolidinyl),1-(3-(S)-methylamino-pyrrolidinyl), 1-(3-(R)-methylamino-pyrrolidinyl),1-(3-(S)-ethylamino-pyrrolidinyl), 1-(4-dimethylamino-pyrrolidinyl),1-(3-(N-methyl-N-t-butoxycarbonyl-amino-pyrrolidinyl) or1-(2-(3,5-dichlorophenyl)-3-methyl-5-carboxy-1,2,4-triazolyl).

In an embodiment of the present invention, n is an integer from 0 to 1,preferably n is 0. In an embodiment of the present invention m is 0. Inanother embodiment of the present invention m is 1.

In an embodiment of the present invention p is an integer from 0 to 2,preferably p is an integer from 0 to 1. In an embodiment of the presentinvention q is 0. In another embodiment of the present invention, q is1.

In an embodiment of the present invention, R³ is selected from the groupconsisting of aryl and arC₁₋₄alkyl; wherein the aryl or arC₁₋₄alkylgroup is optionally substituted with one to three substituentsindependently selected from halogen, hydroxy, carboxy, C₁₋₄alkyl,C₁₋₄alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano orN(R^(E))₂. Preferably, R³ is aryl; wherein the aryl group is optionallysubstituted with one or more substituents independently selected fromhalogen. More preferably, R³ is selected from the group consisting ofphenyl and 4-fluorophenyl.

In an embodiment of the present invention, L¹ is C₁₋₄alkyl; wherein theC₁₋₄alkyl group is optionally substituted with one to two substituentsindependently selected from hydroxy, fluoro, C₁₋₄alkyl, fluorinatedC₁₋₄alkyl or C₁₋₄alkoxy. Preferably, L¹ is unsubstituted C₁₋₄alkyl. Morepreferably, L¹ is selected from the group consisting of —CH₂—, —CH(CH₃)—and —CH₂CH₂—. More preferably still, L¹ is —CH₂— or —CH₂CH₂—;

In an embodiment of the present invention,

is selected from the group consisting of partially unsaturatedcarbocyclyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl.

In another embodiment of the present invention,

is selected from the group consisting of cyclooctyl, 1-acenaphthenyl,R-1-acenaphthenyl, S-1-acenaphthenyl, cyclohexyl, phenyl, 1-naphthyl,2-naphthyl, 1,2,3,4-tetrahydro-naphthyl, 2-thienyl, benzothienyl,4,5,6,7-tetrahydro-benzothienyl, bicyclo[3.1.1 ]hepten-2-yl,bicyclo[3.1.1 ]heptyl and (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl.Preferably,

is selected from the group consisting of cyclooctyl, 1-acenaphthenyl,R-1-acenaphthenyl, S-1-acenaphthenyl, cyclohexyl, phenyl, 1-naphthyl,2-naphthyl, 2-thienyl and (3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl.

In another embodiment of the present invention,

is selected from the group consisting of cyclooctyl, 1-acenaphthenyl,R-1-acenaphthenyl, S-1-acenaphthenyl, cyclohexyl, phenyl, 1-naphthyl and(3a-S)-2,3,3a,4,5,6-hexahydro-1H-phenalen-2-yl.

In another embodiment of the present invention,

is selected from the group consisting of cyclooctyl, 1-naphthyl,1-acenaphthenyl, R-1-acenaphthenyl, S-1-acenaphthenyl,bicyclo[3.1.1]hepten-2-yl and(3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl.

In an embodiment of the present invention, R⁵ is selected from the groupconsisting of hydroxy, carboxy, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, nitro,cyano, N(R^(E))₂, trifluoromethyl, trifluoromethoxy, C₁₋₄alkoxycarbonyl,—SO—N(R^(E))₂, —SO₂—N(R^(E))₂ and —C(O)—N(R^(E))₂.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of halogen, C₁₋₄alkyl and trifluoromethyl. Preferably,R⁵ is selected from the group consisting of chloro, methyl, n-propyl andtrifluoromethyl.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of methyl, n-propyl, chloro and trifluoromethyl.Preferably, R⁵ is selected from the group consisting of methyl, n-propyland trifluoromethyl. More preferably, R⁵ is selected from the groupconsisting of methyl and n-propyl. In yet another embodiment of thepresent invention, R⁵ is methyl.

In an embodiment of the present invention R⁶ is -(L²)₀-R⁷. In anotherembodiment of the present invention, R⁶ is -(L²)₁-R⁷ and L² is selectedfrom the group consisting of —C₁₋₄alkyl-, —O—, —S—, —N(R^(E))—, —C(O)O—and —O—C(O)—.

In an embodiment of the present invention, R⁷ is selected from the groupconsisting of cycloalkyl, aryl, heteroaryl and heterocycloalkyl; whereinthe aryl, heteroaryl or heterocycloalkyl group is optionally substitutedwith one to two substituents independently selected from hydroxy,carboxy, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, N(R^(E))₂,trifluoromethyl, trifluoromethoxy or C₁₋₄alkoxycarbonyl. Preferably, R⁷is selected from the group consisting of aryl and heteroaryl. Morepreferably, R⁷ is selected from the group consisting of phenyl and2-thienyl. More preferably still, R⁷ is 2-thienyl.

In an embodiment of the present invention is a compound of formula (I)selected from the group consisting of

-   8-(R)    acenaphthen-1-yl-3-(3-amino-2-(S)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   8-(R)    acenaphthen-1-yl-3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   8-(R)-Acenaphthen-1-yl-3-(3-dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   3-(3-Dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   8-(R)-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-hydroxymethyl-piperidin-1-yl)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-one;-   3-(3-Amino-2-(R)-hydroxy-propyl)-8-cyclooctyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-1-(S)-(3aS)-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-hydroxy-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-methylamino-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;-   3-[3-(3-Dimethylamino-propylamino)-2-(R)-hydroxy-propyl]-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one    and pharmaceutically acceptable salts thereof.

With regard to compounds of formula (E), in an embodiment of the presentinvention Y is selected from the group consisting of hydrogen, C₁₋₄alkyland t-butoxycarbonyl, preferably, C₁₋₄alkyl or t-butoxycarbonyl, morepreferably ethyl. In another embodiment of the present invention Y is

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. R⁰, R³, n, R⁴, m, L¹,

p, R⁵, q, R⁶and Y) are independently selected to be any individualsubstituent or any subset of substituents selected from the completelist as defined herein.

As used herein, unless otherwise noted, “halogen” shall mean chlorine,bromine, fluorine and iodine.

As used herein, the term “alkyl”, whether used alone or as part of asubstituent group, include straight and branched alkyl chain, preferablycomprising one to eight carbon atoms. For example, alkyl radicalsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,t-butyl, pentyl and the like. As used herein, the term. “lower alkyl”shall mean a straight or branched alkyl chain comprising one to fourcarbon atoms. Suitable examples of a lower alkyl group include methyl,ethyl, propyl, isopropyl, butyl, t-butyl, and the like.

As used herein, unless otherwise noted, the term “hydroxy substitutedalkyl” shall mean any straight or branched alkyl chain which issubstituted with one or more hydroxy groups, for example hydroxymethyl,1-hydroxy-eth-2-yl, and the like. Preferably, the alkyl chain issubstituted with one to three hydroxy groups, more preferably onehydroxy group.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “arC₁₋₄alkyl” shall mean anylower alkyl group (i.e. C₁₋₄alkyl group) substituted with an aryl groupsuch as phenyl, naphthyl and the like. Suitable examples of anarC₁₋₄alkyl group include, benzyl, 2-phenylethyl (i.e. Phenyl-CH₂—CH₂—),3-phenyl-n-propyl (i.e. Phenyl-CH₂—CH₂—CH₂—), naphthyl-methyl, and thelike.

As used herein, unless otherwise noted, the term “acyl” shall mean aradical formed from an organic acid by removal of the hydroxy group.Suitable example include acetyl, benzoyl, and the like.

As used herein, unless otherwise noted, the term “cycloalkyl” shall meanany stable three to fourteen membered monocyclic, bicyclic, tricyclic orbridged carbon based, saturated ring system, for example cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,adamantanyl, bicyclo[3.1.1]heptyl, and the like.

As used herein, unless otherwise noted, the term “carbocyclyl” shallmean four to fourteen membered, preferably five to thirteen membered,more preferably five to ten membered monocyclic, bicyclic or tricyclic,carbon based ring structure. Similarly, unless otherwise noted, the term“partially unsaturated carbocyclyl” shall mean any five to fourteen,preferably five to thirteen, more preferably five to ten, memberedmonocyclic, bicyclic or tricyclic, carbon based ring structurecontaining at least one unsaturated (double or triple) bond. Suitableexamples of partially unsaturated carbocyclyl groups include1,2,3,4-tetrahydronaphthyl, cyclohexen-1-yl, 1-acenaphthenyl,

and the like.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive to seven, preferably five to six, membered monocyclic aromatic ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered bicyclic aromatic ring structure containingat least one heteroatom selected from the group consisting of O, N andS, optionally containing one to four additional heteroatomsindependently selected from the group consisting of O, N and S. Theheteroaryl group may be attached at any heteroatom or carbon atom of thering such that the result is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like. Preferred heteroaryl groupsinclude thienyl, pyridyl, furyl, imidazolyl, pyrazolyl, pyrrolyl,indolyl and quinolinyl.

One skilled in the art will recognize that wherein the heteroaryl groupcontains one or more nitrogen atoms, said heteroaryl group mayoptionally be present as or within a substituent group in a quaternaryform, for example as in1-(2-(3,5-dichlorophenyl)-3-methyl-5-carboxy-1,2,4-triazolyl), asubstituent of the formula

As used herein, the term “heterocycloalkyl” shall denote any five toseven, preferably five to six, membered monocyclic, saturated orpartially unsaturated ring structure containing at least one heteroatomselected from the group consisting of O, N and S, optionally containingone to three additional heteroatoms independently selected from thegroup consisting of O, N and S; or a nine to ten membered saturated,partially unsaturated or partially aromatic bicyclic ring systemcontaining at least one heteroatom selected from the group consisting ofO, N and S, optionally containing one to four additional heteroatomsindependently selected from the group consisting of O, N and S. Theheterocycloalkyl group may be attached at any heteroatom or carbon atomof the ring such that the result is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,4,5,6,7-tetrahydro-benzo[b]thienyl and the like. Preferredheterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,4,5,6,7-tetrahydro-benzo[b]thienyl, 3,4-methylenedioxyphenyl and3,4-dihydro-2H-benzo[b][1,4]dioxepine.

As used herein, the name “1-acenaphthenyl” shall mean a substituentgroup of the formula

As used herein, the name “2-(3,4-methylenedioxyphenyl)ethyl” shall meana substituent group of the formula

As used herein, the name“2-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinyl)” shall mean asubstituent group of the formula

As used herein, the name “2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl” shallmean a substituent group of the formula

As used herein, the name “oxarinyl-methyl” shall mean a substituentgroup of the formula

As used herein, the name “6,6-dimethyl-bicyclo[3.1.1]heptyl” shall meana substituent group of the formula

As used herein, the name “6,6-dimethyl-bicyclo[3.1.1]hept-2-enyl” shallmean a substituent group of the formula

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., alkyl, aryl,carbocyclyl, heterocycloalkyl, heteroaryl), that group may have one ormore substituents, preferably from one to five substituents, morepreferably from one to three substituents, most preferably from one totwo substituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

AcCN = Acetonitrile BINAP = 2,2′-Bis(diphenylphosphino)-1,1′-binaphthylBoc = t-Butoxycarbonyl CBz = benzyloxycarbonyl (C₆H₅—CH₂—O—C(O)—) DAMGO= Tyr-D-Ala-Gly-N-methyl-Phe-Gly-ol DCC = N,N-dicyclohexylcarbodiimideDCE = Dichloroethane DCM = Dichloromethane DIPEA or DIEA =Diisopropylethylamine DMF = N,N-Dimethylformamide DME =1,2-dimethoxyethane DMSO = Dimethylsulfoxide DPDPE =Tyr-D-Pen-Gly-p-Chloro-Phe-D-Pen[Disulfide Bridge: 2-5] EDCI =1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDTA =Ethylenediaminetetraacetic acid EGTA = Ethyleneglycol-O,O′-bis(2-aminoethyl)- N,N,N′,N′-tetracacetic acid EtOAc = Ethylacetate Fmoc = 9-Fluorenylmethoxycarbonyl HBTU =O-(1H-Benzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate hex = Hexane HPLC = High Pressure LiquidChromatography KO-t-Bu = Potassium t-butoxide LiHMDS = Lithiumbis(trimethylsilyl)amide mCPBA = meta-chloroperoxybenzoic acid MeCN =Acetonitrile Ms = mesyl or methanesulfonyl group μW = Microwave NaHMDS =Sodium bis(trimethylsilyl)amide NatBuO or tBuONa = Sodium t-butoxide NMP= N-methyl-2-pyrrolidinone Pd₂(dba)₃ = Tris(dibenzylideneacetone)dipalladium (0) Pd(OAc)₂ = Palladium (II) acetate Pd(PPh₃)₄ =tetrakis(triphenylphosphine)palladium(0) PdCl₂(PPh₃)₂ or =di(chloro)di(triphenylphosphine)palladium(0) Pd(PPh₃)₂Cl₂ P(tBu)₃ =Tri-t-butyl phosphine PEI = Polyethylimine TEA or Et₃N = TriethylamineTFA = Trifluoroacetic acid THF = Tetrahydrofuran TLC = Thin LayerChromatography TNE Buffer = 50 mM Tris-HCl, pH 7.4 + 5 mM EDTA + 150 mMNaCl Tris HCl = Tris[hydroxymethyl]aminomethyl hydrochloride Ts = Tosylor p-toluenesulfonyl group U69593 =(+)-(5α,7α,8β)-N-methyl-N-7-(1-pyrrolidinyl)-1- oxaspiro[4.5]dec-8-yl]benzene acetamide

As used herein, unless otherwise noted, the term “eating disorders”shall mean any disorder associated with eating. Suitable examplesinclude, but are not limited to anorexia nervosa, bulimia, binge eating,food cravings, and the like.

As used herein, unless otherwise noted, the term “adrenal disorders”shall mean disorders mediated by the adrenal gland. Suitable examplesinclude, but are not limited to Cushing's syndrome, Addison's disease,and the like.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is or has been the object oftreatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, carnsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, tosylate,triethiodide and valerate.

The compounds of formula (I) of the present invention may be preparedaccording to the processes described in more detail herein. Moreparticularly, the compounds of formula (I) may be prepared throughintermediates of formula (M1) or (M2), as outlined in Scheme 1.

More particularly, a suitably substituted compound of formula (II), aknown compound or compound prepared by known methods, is reacted toyield the compound of formula (M1), which is then further reacted toyield the corresponding compound of formula (I).

Alternatively, the compound of formula (II) is reacted to yield thecorresponding compound of formula (M2), which is further reacted toyield the corresponding compound of formula (I).

One skilled in the art will recognize that in the processes outlinedabove, more particularly in the reaction of a compound of formula (II)to form the compound of formula (M1), the N atom at the 8 position ofthe 1,3,8-triazaspiro[4.5]decan-4-one core is preferably protected, byknown methods, with a known protecting group such as BOC, Fmoc, CBz,benzoyl, benzhydryl, and the like. One skilled in the art will furtherrecognize that when a protecting group is utilized in the preparation ofthe compound of formula (M1), the protecting group is removed, by knownmethods, prior to reacting the compound of formula (M1) to yield thecompound of formula (I).

One skilled in the art will recognize that the processes hereinafteroutlined in Schemes 2 to 7 incorporate the R⁰ or “top” substituentportion of the molecule onto the core structure, whereas Schemes 8 to 14incorporate the

or “bottom” substituent portion of the molecule onto the core structure.One skilled in the art will further recognize that the top and bottomsubstituent portions may be incorporated into the compound of formula(I) in any order which yields the desired product.

Compounds of formula (M1) wherein R⁰ is —CR^(A)R^(B)—CH(OH)—CR^(C)R^(D)

—X and X is NR¹R² may be prepared from a suitably substituted compoundof formula (II) according to the process outlined in Scheme 2.

Accordingly, a suitably substituted compound of formula (II), isprotected by known methods, with a suitably protecting group PG¹, suchas t-butoxycarbonyl (BOC), CBz, Fmoc, benzhydryl, triphenylmethyl,4-methoxybenzyl, benzoyl, and the like, to yield the correspondingcompound of formula (III).

The compound of formula (III) is reacted with a suitable substitutedcompound of formula (IV) wherein Q is a suitable leaving group such asCl, Br, I, tosylate, mesylate, and the like, a known compound orcompound prepared by known methods, in the presence of a base such asNaH, KO-t-Bu, K₂CO₃, NaHMDS, LiHMDS, and the like, in an organic solventsuch as NMP, DMF, THF, and the like, to yield the corresponding compoundof formula (V).

The compound of formula (V) is reacted with a suitably substituted amineof formula (VI), a known compound or compound prepared by known methods,in an organic solvent such as ethanol, acetonitrile, methanol,isopropanol, and the like, to yield the corresponding compound offormula (VII).

The compound of formula (VII) is de-protected by known methods, to yieldthe corresponding compound of formula (M1a).

One skilled in the art will recognize that in the preparation ofcompounds of formula (I) and (M1a) as in Scheme 2 above (i.e. inreactions where the oxarinyl group is opened with a suitably substitutedcompound of formula (VI)), the stereo-configuration of the hydroxy groupwill be determined by the stereo-configuration of the compound offormula (IV), with the naming (R or S) of the stereo-center based onchemical nomenclature rules. Thus, for example, wherein the processoutlined in Scheme 2 above R¹, R², R^(A), R^(B), R_(C) and R^(D) areeach hydrogen, the compound of formula (IV) is2-(R)-chloromethyl-oxirane, then the compound of formula (M1a) will havethe hydroxy group in the (R) position.

Compounds of formula (M1a) wherein R⁰ is

may be similarly prepared according to the process outlined in Scheme 2above, with substitution of a suitably substituted compound of formula(VIII)

wherein Q is a suitable leaving group as previously defined, a knowncompound or compound prepared by known methods, for the compound (IV).

Compounds of formula (M1) wherein X is —O—R¹ may be prepared from asuitably substituted compound of formula (V) according to the processoutlined in Scheme 3.

Accordingly, a suitably substituted compound of formula (V), is reactedwith suitably substituted compound of formula (IX), a known compound orcompound prepared by known methods, in the presence of a base such asNaH, KH, sodium trimethylsilylamide, TEA, DIPEA, and the like, whereinthe base is present in amount equal to or greater than about one molarequivalent, in an organic solvent such as THF, NMP, DMF, and the like,to yield the corresponding compound of formula (X).

The compound of formula (X) is de-protected, by known methods, to yieldthe corresponding compound of formula (M1b).

Compounds of formula (M1) wherein X is selected from the groupconsisting of —S—R¹, —SO—R¹ or —SO₂—R¹ may be prepared from a suitablysubstituted compound of formula (V) according to the process outlined inScheme 4.

Accordingly, a suitably substituted compound of formula (V) is reactedwith a suitably substituted compound of formula (XI), a known compoundor compound prepared by known methods, in the presence of a base such asTEA, DIPEA, and the like, in a protic solvent such as ethanol, methanol,NMP, and the like, or a mixture thereof, preferably at an elevatedtemperature in the range of about room temperature to about 100° C.,preferably at a temperature of about 50 to about 100° C., to yield thecorresponding compound of formula (XII).

The compound of formula (XII) is de-protected by known methods, to yieldthe corresponding compound of formula (M1c), wherein X is —S—R¹.

Alternatively, the compound of formula (XII) is oxidized with anoxidizing agent such as hydrogen peroxide, mCPBA, and the like,according to known methods, to yield the corresponding compound offormula (XIII).

The compound of formula (XIII) is de-protected by known methods, toyield the corresponding compound of formula (M1d), wherein X is —SO—R¹or —SO₂—R¹.

One skilled in the art will recognize that in the processes described inScheme 4 above, the PG¹ protecting group on the N atom at the 8-positionof the 1,3,8-triazaspiro[4.5]decan-4-one is not mandatory (but may bepreferred), as the reactions will yield the desired compounds even inthe absence of protection of the N atom.

One skilled in the art will recognize that compounds of formula (M1)wherein X is selected from —S-(alkyl)-NR¹R², —SO-(alkyl)-NR¹R² or—SO₂-(alkyl)-NR¹R² may be similarly prepared according to the processoutlined in Scheme 4 above, with substitution of a suitably substitutedcompound of formula (XIV)HS-(alkyl)-NR¹R²  (XIV),

a known compound or compound prepared by known methods, for the compoundof formula (XI).

Compounds of formula (M1) wherein X is —NR¹—C(O)—R² may be preparedaccording to the process outlined in Scheme 5.

Accordingly, a suitably substituted compound of formula (VII), whereinR¹ is hydrogen, is reacted with a suitably substituted compound offormula (XV), wherein Z is Cl, Br or OH, a known compound or compoundprepared by known methods, in the presence of a base such as TEA, DIPEA,pyridine, and the like, wherein the base is present in an amount equalto or greater than about one molar equivalent, in an organic solventsuch as THF, DMF, NMP, DCM, and the like, preferably at roomtemperature, to yield the corresponding compound of formula (XVI).Wherein the compound of formula (XV) Z is OH, the compound of formula(VII) is reacted with the compound of formula (XV) in the presence of acoupling agent such as HBTU, DCC, and the like.

The compound of formula (XVI) is de-protected by known methods, to yieldthe corresponding compound of formula (M1e).

Compounds of formula (M1) wherein X is —C(O)—NR¹NR² may be preparedaccording to the process outlined in Scheme 6.

Accordingly, a suitably substituted compound of formula (V) is reactedwith potassium cyanide, in a co-solvent such as methanol-water, and thelike, preferably at room temperature, to yield the correspondingcompound of formula (XVII).

The compound of formula (XVII) is reacted with a base such as KOH, NaOH,and the like or with an acid such as H₂SO₄, HCl, and the like, or NaBH₄in the presence of AlCl₃, to yield the corresponding compound of formula(XVIII).

The compound of formula (XVIII) is reacted with a suitably substitutedcompound of formula (VI), a known compound or compound prepared by knownmethods, in the presence of a coupling agent such as DCC, EDCl, and thelike, in an organic solvent such as CH₂Cl₂, THF, DMF, and the like, toyield the corresponding compound of formula (XIX).

The compound of formula (XIX) is de-protected by known methods, to yieldthe corresponding compound of formula (M1f).

Alternatively, the compound of formula (XVII) is reacted with a suitablysubstituted alcohol, a compound of the formula R¹—OH, a known compoundor compound prepared by known methods, in the presence of an acid suchas acetic acid, H₂SO₄, HCl, and the like, to yield the correspondingcompound of formula (M1) wherein X is C(O)NHR¹. One skilled in the artwill recognize that compounds of formula (M1) wherein X is C(O)N(R¹)₂may be similarly prepared by reacting the compound of formula (XVII)with a suitably substituted alcohol of the formula R¹—OH, in thepresence of an acid such as H₂SO₄, HCl, and the like, wherein thealcohol of formula R¹—OH is present in an excess amount.

Compounds of formula (M1a) wherein R⁰ is

may alternatively be prepared according to the process outlined inScheme 7.

Accordingly, a suitably substituted compound of formula (III), isreacted with a suitably substituted compound of formula (XX), wherein Qis a suitable leaving group such as Cl, Br, I, tosylate, mesylate, andthe like, and wherein PG² is a suitably protecting group such as benzyl,acyl, and the like, a known compound or compound prepared by knownmethods, in the presence of a base such as NaH, KO-t-Bu, K₂CO₃, NaHMDS,LiHMDS, and the like, in an organic solvent such as NMP, DMF, THF, andthe like, to yield the corresponding compound of formula (XXI).

The compound of formula (XXI) is de-protected by known methods, to yieldthe corresponding compound of formula (M1a). One skilled in the art willrecognize that the protecting groups PG¹ and PG² on the compound offormula (XXI) may be removed simultaneously or sequentially, in anyorder, by known methods.

One skilled in the art will recognize, that compounds of formula (M1)wherein R⁰ is selected from the group consisting of

may be similarly prepared according to the process outlined in Scheme 7above, with selection and substitution of a suitably substitutedcompound of formula (XXII)

or the compound of formula (XXIII),

respectively, for the compound of formula (XX).

One skilled in the art will recognize that the processes outlined inSchemes 2 to 7 above may be similarly applied to the preparation ofcompounds of formula (I) with substitution of a suitably substitutedcompound of formula (M2) for the compound of formula (II).

Compounds of formula (M2), wherein m is an integer from 0 to 1, providedthat when

is aryl or heteroaryl, then m is 1, may be prepared according to theprocess outlined in Scheme 8.

Accordingly, a suitably substituted compound of formula (II), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XXIV), a known compound orcompound prepared by known methods, in the presence of a base such asTEA, DIPEA, pyridine, Na₂CO₃, K₂CO₃, and the like, wherein the base ispresent in an amount equal to or greater than about one molarequivalent, in an organic solvent such as DMF, DMSO, NMP, and the like,to yield the corresponding compound of formula (M2).

Compounds of formula (M2) wherein m is 0 and

is aryl or heteroaryl may be prepared according to the process outlinedin Scheme 9.

Accordingly, a suitably substituted compound of formula (II), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XXV), wherein Q is a suitableleaving group such as Cl, Br, I, triflate, and the like, a knowncompound or compound prepared by known methods, in the presence of acatalyst such as Pd(OAc)₂, Pd₂(dba)₃, and the like, in the presence of aphosphine ligand such as BINAP, P(tBu)₃, and the like, in the presenceof a base such as Na₂CO₃, tBuONa, and the like, in an organic solventsuch as toluene, dioxane, and the like, preferably at an elevatedtemperature in the range of about 30 to about 120° C., to yield thecorresponding compound of formula (M2a).

Compounds of formula (M2) may alternatively be prepared according to theprocess outlined in Scheme 10.

Accordingly, a suitably substituted compound of formula (II), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XXVI), a known compound orcompound prepared by known methods, in the presence of a base such asTEA, DIPEA, pyridine, Na₂CO₃, K₂CO₃, and the like, wherein the base ispresent in an amount equal to or greater than about one molarequivalent, in an organic solvent such as DMF, DMSO, NMP, and the like,to yield the corresponding compound of formula (XXVII).

The compound of formula (XXVII) is reacted with a suitably substitutedboronic acid, a compound of formula (XXVIII), a known compound orcompound prepared by known methods, in the presence of a catalyst suchas Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, and the like, in the presence of a base suchas Na₂CO₃, K₃PO₄, and the like, in a non-protic organic solvent ormixture thereof, such as toluene, DME, DMF, and the like, or a mixturethereof such as toluene/ethanol, and the like, to yield thecorresponding compound of formula (M2).

One skilled in the art will recognize that for compounds of formula(XXVI), the Br may alternatively be replaced with an I or triflate.

Compounds of formula (M2) wherein m is 1, L¹ is C₁₋₆alkyl orC₃₋₆alkenyl, R⁶ is (L²)₀-R⁷ and R⁷ is an aryl or heteroaryl group may beprepared according to the process outlined in Scheme 11.

Accordingly, a suitably substituted compound of formula (II), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted aldehyde, a compound of formula (XXIX), wherein Dis C₁₋₅alkyl or C₂₋₅alkenyl, a known compound or compound prepared byknown methods, in the presence of a reducing agent such as sodiumtriacetoxyborohydride, sodium cyanoborohydride, and the like, in thepresence of an acid such as acetic acid, and the like, in an organicsolvent such as DCE, THF, acetonitrile, and the like, to yield thecorresponding compound of formula (M2a).

Compounds of formula (XXIX) may be prepared according to the processesoutlined in Scheme 12.

Accordingly, a suitably substituted compound of formula (XXX), wherein Dis C₁₋₅alkyl or C₂₋₅alkenyl, a known compound or compound prepared byknown methods, is reacted with a suitably substituted boronic acid, acompound of formula (XXXI), a known compound or compound prepared byknown methods, in the presence of a catalyst such as Pd(PPh₃)₄,Pd(PPh₃)₂Cl₂, and the like, in the presence of a base such as Na₂CO₃,NaHCO₃, K₃PO₄, and the like, in a non-protic organic solvent or mixturethereof such as toluene, toluene/ethanol, DME, DMF, benzene, and thelike, to yield the corresponding compound of formula (XXIX).

Alternatively, a suitably substituted compound of formula (XXXII),wherein D is C₁₋₅alkyl or C₂₋₅alkenyl, a known compound or compoundprepared by known methods, is reacted with a suitably substitutedcompound of formula (XXXIII), a known compound or compound prepared byknown methods, in the presence of a catalyst such as Pd(PPh₃)₄,PdCl₂(PPh₃)₂, and the like, in the presence of a base such as aqueousNaHCO₃, Na₂CO₃, K₃PO₄, and the like, in an organic solvent such as DME,DMF, toluene, benzene, and the like, to yield the corresponding compoundof formula (XXIX).

One skilled in the art will recognize that for compounds of formula(XXXI) and/or compounds of formula (XXXIII), the Br may alternatively bereplaced with an I or triflate.

Compounds of formula (M2) wherein q is 1, R⁶ is (L²)₁-R⁷ and L² is —O—may be prepared according to the process outlined in Scheme 13.

Accordingly, a suitably substituted compound of formula (XXXIV), whereinD is C₁₋₅alkyl or C₂₋₅alkenyl, a known compound or compound prepared byknown methods, is reacted with a suitably substituted alcohol, acompound of formula (XXXV), a known compound or compound prepared byknown methods, in the presence of an activating agent such astributylphosphine, triphenylphosphine, diphenyl-2-pyridylphosphine, andthe like, in an anhydrous organic solvent such as benzene, THF, DCM, andthe like, (via a Mitsunobu reaction) in the presence of a dehydratingagent such as 1,1′-(azodicarbonyl)dipiperidine, diethylazodicarboxylate,diisopropylazodicarboxylate, and the like, to yield the correspondingcompound of formula (XXXVII).

Alternatively, the compound of formula (XXXVII) may be prepared byreacting a compound of formula (XXXIV) with a compound of formula(XXXV), wherein the hydroxy (OH) group on the compound of formula (XXXV)is replaced with a fluoro, bromo or triflate, in the presence of a basesuch as K₂CO₃, sodium carbonate, sodium bicarbonate, and the like, in adipolar aprotic solvent such as (CH₃)₂NCOCH₃, DMF, DMSO, and the like.

Alternatively, the compound of formula (XXXIV) is reacted with asuitably substituted boronic acid, a compound of formula (XXXVI), aknown compound or compound prepared by known methods, in the presence ofa catalyst such as copper (II) acetate, and the like, in the presence ofan base such as TEA, pyridine, and the like, in the presence ofmolecular sieves, preferably 4 Angstrom molecular sieves, in an organicsolvent such as DCM, DCE, and the like, preferably at ambienttemperature, to yield the corresponding compound of formula (XXXVII).

The compound of formula (XXXVII) is reacted with a suitably substitutedcompound of formula (II), a known compound or compound prepared by knownmethods, in the presence of a reducing agent such as sodiumtriacetoxyborohydride, sodium cyanoborohydride, and the like, in anorganic solvent such as DCE, THF, acetonitrile, and the like, to yieldthe corresponding compound of formula (M2b).

One skilled in the art will recognize that compounds of formula (M2)wherein L² is —S— may similarly be prepared according to the processoutlined above with appropriate selection and substitution of suitablysubstituted starting materials (e.g. substitution of the OH group on thecompound of formula (XXXIV) with Cl or Br and substitution of a suitablysubstituted compound of the formula R⁷—SH for the compound of formula(XXXV), preferably in the presence of a copper catalyst, according toknown methods. The sulfur group may then be further oxidized with asuitable oxidizing agent such as hydrogen peroxide, mCPBA, and the like,according to known methods, to yield the corresponding compound whereinL² is selected from —SO— or —SO₂—.

Compounds of formula (M2) wherein R⁶ is -L²-R⁷ and L² is C₂₋₄alkenyl maybe prepared according to the process outlined in Scheme 14.

Accordingly, a suitably substituted compound of formula (XXXVIII), aknown compound or compound prepared by known methods, is reacted with asuitably substituted boronic acid, a compound of formula (XXVIII), aknown compound or compound prepared by known methods, in the presence ofa catalyst such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, and the like, in thepresence of a base such as NaHCO₃, K₂CO₃, Na₂CO₃, and the like, to yieldthe corresponding compound of formula (XXXIX).

The compound of formula (XXXIX) is reacted with methanesulfonylchloride, a known compound, in the presence of an organic base such asTEA, DIPEA, N-methylmorpholine, and the like, in an aprotic solvent suchas DCM, THF, acetonitrile, CHCl₃, and the like, to yield thecorresponding compound of formula (XXXX), wherein Ms is a mesyl group.

The compound of formula (XXXX) is reacted with a suitably substitutedcompound of formula (II), a known compound or compound prepared by knownmethods, in the presence of a reducing agent such as sodiumtriacetoxyborohydride, sodium cyanoborohydride, and the like, in anorganic solvent such as DCM, DCE, THF, methanol, acetonitrile, and thelike, to yield the corresponding compound of formula (M2c).

One skilled in the art will recognize that the processes outlined inSchemes 8 to 14 above may be similarly applied to the preparation ofcompounds of formula (I) with substitution of a suitably substitutedcompound of formula (M1) for the compound of formula (II).

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in Design of Prodrugs. ed. H. Bundgaard, Elsevier, 1985.

Following the procedures described herein, representative compounds ofthe present invention were prepared as listed in Tables 1-8. In theTables below, the column headed with a * shall define the stereochemicalconfiguration of the bond denoted with the “*” symbol in the generalstructure at the head of the table. In addition to “R” and “S”designations, racemic mixtures will be denoted with the term “Rac”. Forthe

substituent, the stereoconfiguration is racemic, unless otherwise notedwith an “R” or “S”. In the columns headed (L¹)_(m), a listing of“absent” shall mean that m is 0.

TABLE 1

ID# * R² R³ (L¹)_(m)

1 S 2-(4-morpholinyl) 4-fluorophenyl CH₂ cyclooctyl ethyl 2 R3,4-dimethoxy benzyl 4-fluorophenyl CH₂ cyclooctyl 3 R 3,5-di(trifluoro4-fluorophenyl CH₂ cyclooctyl methyl)benzyl 4 R 2-(4-imidazolyl) ethyl4-fluorophenyl CH₂ cyclooctyl 5 R 4-bromobenzyl 4-fluorophenyl CH₂cyclooctyl 6 R 3,4-dimethoxy benzyl 4-fluorophenyl CH₂ cyclooctyl 7 S2,4-difluorobenzyl 4-fluorophenyl CH₂ cyclooctyl 8 S 2,4-dimethoxybenzyl 4-fluorophenyl CH₂ cyclooctyl 9 S 4-biphenyl 4-fluorophenyl CH₂cyclooctyl 10 S 2-ethoxybenzyl 4-fluorophenyl CH₂ cyclooctyl 11 S2-phenylethyl 4-fluorophenyl CH₂ cyclooctyl 12 S 2,5-difluorobenzyl4-fluorophenyl CH₂ cyclooctyl 13 S 2-(5-bromopyridyl) 4-fluorophenyl CH₂cyclooctyl 14 S 2-methoxybenzyl 4-fluorophenyl CH₂ cyclooctyl 15 S4-bromobenzyl 4-fluorophenyl CH₂ cyclooctyl 16 S 3,5-di(trifluoro4-fluorophenyl CH₂ cyclooctyl methyl)benzyl 17 S 1-adamantanyl-4-fluorophenyl CH₂ cyclooctyl methyl 18 S 3-methylbenzyl 4-fluorophenylCH₂ cyclooctyl 19 S 2-(2,5-dimethoxy-2,5- dihydro-furyl)-methyl4-fluorophenyl CH₂ cyclooctyl 20 S 3-bromobenzyl 4-fluorophenyl CH₂cyclooctyl 21 S 3-chlorobenzyl 4-fluorophenyl CH₂ cyclooctyl 22 S3,4-dimethoxy benzyl 4-fluorophenyl CH₂ cyclooctyl 23 S 4-nitrobenzyl4-fluorophenyl CH₂ cyclooctyl 24 S 4-pyridyl 4-fluorophenyl CH₂cyclooctyl 25 S 3,5-dimethoxy-benzyl 4-fluorophenyl CH₂ cyclooctyl 26 S2-(2-thienyl)ethyl 4-fluorophenyl CH₂ cyclooctyl 27 S 2-methylbenzyl4-fluorophenyl CH₂ cyclooctyl 28 S 2-(4-imidazolyl)-ethyl 4-fluorophenylCH₂ cyclooctyl 29 S 4-trifluoromethyl 4-fluorophenyl CH₂ cyclooctylbenzyl 30 S 2-(4-bromophenyl) 4-fluorophenyl CH₂ cyclooctyl ethyl 31 S2,4-dichlorobenzyl 4-fluorophenyl CH₂ cyclooctyl 32 S 3-pyridylmethyl4-fluorophenyl CH₂ cyclooctyl 33 S 3-trifluoromethyl 4-fluorophenyl CH₂cyclooctyl benzyl 34 S 2-(4-methoxy- 4-fluorophenyl CH₂ cyclooctylphenyl)ethyl 35 S 3-methoxybenzyl 4-fluorophenyl CH₂ cyclooctyl 36 S4-pyridyl 4-fluorophenyl CH₂ cyclooctyl 38 S 2-(3,4-dimethoxy4-fluorophenyl CH₂ cyclooctyl phenyl)ethyl 39 S 2-pyridylmethyl4-fluorophenyl CH₂ cyclooctyl 40 S 1-naphthyl 4-fluorophenyl CH₂cyclooctyl 41 S 4-methylbenzyl 4-fluorophenyl CH₂ cyclooctyl 42 S2-(3,5-dimethyl- 4-fluorophenyl CH₂ cyclooctyl pyridyl) 43 S3,4,5-trimethoxy- 4-fluorophenyl CH₂ cyclooctyl benzyl 44 S2-bromobenzyl 4-fluorophenyl CH₂ cyclooctyl 45 S 2,3-dimethoxy benzyl4-fluorophenyl CH₂ cyclooctyl 46 S 3,4-dichlorobenzyl 4-fluorophenyl CH₂cyclooctyl 47 R 2-(4-morpholinyl) 4-fluorophenyl absent 1-acenaphthenylethyl 48 S 2-(3,4-dimethoxy- 4-fluorophenyl absent 1-acenaphthenylphenyl)ethyl 49 S 2-(3,4-dimethoxy- 4-fluorophenyl absent4-n-propyl-cyclohexyl phenyl)ethyl 50 S 2-(4-morpholinyl) 4-fluorophenylCH₂CH₂ phenyl ethyl 51 S 2-(3,4-dimethoxy- 4-fluorophenyl CH₂CH₂ phenylphenyl)ethyl 52 Rac 2-(3,4-dimethoxy- phenyl absent 1-acenaphthenylphenyl)ethyl 53 R 2-(4-morpholinyl) phenyl absent 1-acenaphthenyl ethyl251 S 2-(4-morpholinyl) 4-fluorophenyl CH₂ 1-naphthyl ethyl 253 S2-(3,4-dimethoxy- 4-fluorophenyl CH₂ 1-naphthyl phenyl)ethyl 254 S2-(3,4-methylene 4-fluorophenyl CH₂ 1-naphthyl dioxyphenyl)ethyl 255 S2-(2-nitro-4,5- 4-fluorophenyl CH₂ 1-naphthyl dimethoxy-phenyl) ethyl259 S 2-(4-morpholinyl) 4-fluorophenyl CH₂ 2-naphthyl ethyl 261 S2-(3,4-dimethoxy- 4-fluorophenyl CH₂ 2-naphthyl phenyl)ethyl 262 S2-(3,4-methylene 4-fluorophenyl CH₂ 2-naphthyl dioxyphenyl)ethyl 265 S2-(4-morpholinyl) 4-fluorophenyl CH₂ 4-chlorophenyl ethyl 267 R2-(3,4-dimethoxy- 4-fluorophenyl CH₂ 4-chlorophenyl phenyl)ethyl 268 R2-(3,4-methylene 4-fluorophenyl CH₂ 4-chlorophenyl dioxyphenyl)ethyl 269R 2-(2-nitro-4,5- 4-fluorophenyl CH₂ 4-chlorophenyl dimethoxy-phenyl)ethyl 271 R 2-(3,4-methylene 4-fluorophenyl absent 1-acenaphthenyldioxyphenyl)ethyl 276 S 2-(2-nitro-4,5- 4-fluorophenyl absent1-acenaphthenyl dimethoxy-phenyl) ethyl 279 S 1-(t-butoxy-carbonyl)-4-fluorophenyl CH₂ cyclooctyl 2-phenylethyl 281 S 2-ethoxy-phenyl4-fluorophenyl CH₂ cyclooctyl 282 S 4-((1-phenyl-pyrazol- 4-fluorophenylCH₂ cyclooctyl 2-yl)-aminosulfonyl) phenyl 285 S 4-cyclohexyl-phenyl4-fluorophenyl CH₂ cyclooctyl 292 S 2-(3,4-dimethoxy- 4-fluorophenyl CH₂5-phenyl-2-thienyl phenyl)ethyl 293 S 2-(4-morpholinyl) 4-fluorophenylCH₂ 5-phenyl-2-thienyl ethyl 298 R 2-(4-morpholinyl) 4-fluorophenylabsent 1-acenaphthenyl ethyl 300 R 2-(3,4-dimethoxy- 4-fluorophenylabsent 1-acenaphthenyl phenyl)ethyl 307 S 3,4-dimethoxy-benzyl4-fluorophenyl absent 1-acenaphthenyl 308 S 4-nitrobenzyl 4-fluorophenylabsent 1-acenaphthenyl 309 S 2-(1,2,3,4-tetrahydro- 4-fluorophenylabsent 1-acenaphthenyl isoquinolinyl) 310 S 4-biphenyl 4-fluorophenylabsent 1-acenaphthenyl 311 S 2-furylmethyl 4-fluorophenyl absent1-acenaphthenyl 312 S 3-iodobenzyl 4-fluorophenyl absent 1-acenaphthenyl314 S 3,4-difluorobenzyl 4-fluorophenyl absent 1-acenaphthenyl 315 S3-bromobenzyl 4-fluorophenyl absent 1-acenaphthenyl 316 S 4-chlorobenzyl4-fluorophenyl absent 1-acenaphthenyl 317 S 4-methoxybenzyl4-fluorophenyl absent 1-acenaphthenyl 318 S 2-methoxybenzyl4-fluorophenyl absent 1-acenaphthenyl 319 S 3,5-di(trifluoromethyl)4-fluorophenyl absent 1-acenaphthenyl benzyl 320 S 3,4,5- 4-fluorophenylabsent 1-acenaphthenyl trimethoxybenzyl 321 S 3-fluorobenzyl4-fluorophenyl absent 1-acenaphthenyl 322 S 3-methoxybenzyl4-fluorophenyl absent 1-acenaphthenyl 323 S 2-(4-methoxy- 4-fluorophenylabsent 1-acenaphthenyl phenyl)ethyl 324 S 3,5-dimethoxybenzyl4-fluorophenyl absent 1-acenaphthenyl 325 S 4-methyl-benzyl4-fluorophenyl absent 1-acenaphthenyl 326 S 3-(phenyl)-n-propyl4-fluorophenyl absent 1-acenaphthenyl 327 S 4-pyridyl 4-fluorophenylabsent 1-acenaphthenyl 328 S 4-trifluoromethoxy 4-fluorophenyl absent1-acenaphthenyl benzyl 329 S 2-(phenoxy)ethyl 4-fluorophenyl absent1-acenaphthenyl 330 S 2-methyl-benzyl 4-fluorophenyl absent1-acenaphthenyl 331 S 2,3-dimethoxybenzyl 4-fluorophenyl absent1-acenaphthenyl 338 S 3-di(n-butyl)amino-n- 4-fluorophenyl absent1-acenaphthenyl propyl 341 S 2-phenylethyl 4-fluorophenyl absent1-acenaphthenyl 342 S 2,5-difluoro-benzyl 4-fluorophenyl absent1-acenaphthenyl 343 S 3,4-dichloro-benzyl 4-fluorophenyl absent1-acenaphthenyl 344 S 3-trifluoromethyl 4-fluorophenyl absent1-acenaphthenyl benzyl 345 S benzyl 4-fluorophenyl absent1-acenaphthenyl 346 S 2-fluoro-benzyl 4-fluorophenyl absent1-acenaphthenyl 347 S 4-trifluoromethyl 4-fluorophenyl absent1-acenaphthenyl benzyl 348 S 4-methoxycarbonyl- 4-fluorophenyl absent1-acenaphthenyl benzyl 349 S 2,4-dimethoxybenzyl 4-fluorophenyl absent1-acenaphthenyl 350 S 3-chlorobenzyl 4-fluorophenyl absent1-acenaphthenyl 351 S 3-ethoxybenzyl 4-fluorophenyl absent1-acenaphthenyl 352 S 4-bromobenzyl 4-fluorophenyl absent1-acenaphthenyl 353 S 3-methylbenzyl 4-fluorophenyl absent1-acenaphthenyl 354 S 4-fluorobenzyl 4-fluorophenyl absent1-acenaphthenyl 355 S 2-bromobenzyl 4-fluorophenyl absent1-acenaphthenyl 356 S 2-(3,4-methylene 4-fluorophenyl absent1-acenaphthenyl dioxyphenyl)ethyl 358 S 2,4-difluorobenzyl4-fluorophenyl absent 1-acenaphthenyl 365 S 2-(4-bromophenyl)4-fluorophenyl absent 1-acenaphthenyl ethyl 366 S 3-pyridyl-methyl4-fluorophenyl absent 1-acenaphthenyl 367 S 2,4,6- 4-fluorophenyl absent1-acenaphthenyl trimethoxybenzyl 368 S 2,4-dichlorobenzyl 4-fluorophenylabsent 1-acenaphthenyl 370 S 3-nitrobenzyl 4-fluorophenyl absent1-acenaphthenyl 371 S 1-naphthyl-methyl 4-fluorophenyl absent1-acenaphthenyl 372 S 2-(2-thienyl)ethyl 4-fluorophenyl absent1-acenaphthenyl 373 S 2-trifluoromethyl 4-fluorophenyl absent1-acenaphthenyl benzyl 385 R 2-(3,4-dimethoxy- 4-fluorophenyl CH₂1-(8-methyl-naphtyl) phenyl)ethyl 386 S 2-(3,4-dimethoxy- 4-fluorophenylCH₂ 1-(8-methyl-naphtyl) phenyl)ethyl 387 R 2-(4-morpholinyl)4-fluorophenyl CH₂ 1-(8-methyl-naphtyl) ethyl 374 S

4-fluorophenyl absent 1-acenaphthenyl 375 S 2-(4,6-dimethyl)-4-fluorophenyl absent 1-acenaphthenyl pyridyl 376 S 4-pyridyl-methyl4-fluorophenyl absent 1-acenaphthenyl 378 R 2-pyridyl-methyl4-fluorophenyl absent 1-acenaphthenyl 379 R 4-pyridyl 4-fluorophenylabsent 1-acenaphthenyl 380 R 3-(6-methoxy-pyridyl) 4-fluorophenyl absent1-acenaphthenyl 381 R 3-pyridyl 4-fluorophenyl absent 1-acenaphthenyl383 R 2-(5-methyl-pyridyl) 4-fluorophenyl absent 1-acenaphthenyl 390 R2-(3,4-methylene 4-fluorophenyl CH₂ 1-(8-methyl-naphthyl)dioxyphenyl)ethyl 392 R 4-methoxybenzyl 4-fluorophenyl CH₂1-(8-methyl-naphthyl) 393 R 4-pyridyl 4-fluorophenyl CH₂1-(8-methyl-naphthyl) 396 S 2-(4-morpholinyl) 4-fluorophenyl CH₂1-(8-methyl-naphthyl) ethyl 398 S 4-methoxybenzyl 4-fluorophenyl CH₂1-(8-methyl-naphthyl) 418 S 2-(3,4-methylene dioxyphenyl)ethyl4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 419 S 2-pyridyl 4-fluorophenylabsent 1-acenaphthenyl 420 R H 4-fluorophenyl absent R-1-acenaphthenyl421 R 2-pyridyl 4-fluorophenyl absent R-1-acenaphthenyl 422 S H4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 424 S H 4-fluorophenyl absentR-1-acenaphthenyl 425 R methyl 4-fluorophenyl absent R-1-acenaphthenyl426 R H 4-fluorophenyl absent S-1-acenaphthenyl 427 R methyl4-fluorophenyl absent S-1-acenaphthenyl 430 S H 4-fluorophenyl absentS-1-acenaphthenyl 431 S methyl 4-fluorophenyl absent S-1-acenaphthenyl437 S methyl 4-fluorophenyl absent R-1-acenaphthenyl 438 R H4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 443 S methoxy 4-fluorophenylabsent R-1-acenaphthenyl 444 S ethoxy 4-fluorophenyl absentR-1-acenaphthenyl 446 R 2-(3,4-methylene 4-fluorophenyl absent1-acenaphthenyl dioxyphenyl)ethyl 448 S 2-phenoxyethyl 4-fluorophenylabsent 1-acenaphthenyl 451 S 4-(1-phenyl-2- 4-fluorophenyl CH₂cyclooctyl pyrazolyl-amino- sulfonyl)phenyl 452 S 4-carboxy-benzyl4-fluorophenyl CH₂ cyclooctyl 453 S H 4-fluorophenyl CH₂ cyclooctyl 454S n-butyl 4-fluorophenyl CH₂ cyclooctyl 458 S phenyl 4-fluorophenyl CH₂2-trifluoromethyl-6- chloro-phenyl 461 R 2-(2-nitro-4,5- 4-fluorophenylabsent 1-acenaphthenyl dimethoxy- phenyl)ethyl 463 S benzyloxy4-fluorophenyl absent R-1-acenaphthenyl 464 R 4-(aminoethyl)-phenyl4-fluorophenyl absent S-1-acenaphthenyl 600 S phenyl 4-fluorophenylabsent R-1-acenaphthenyl 601 R 4-(t-butoxycarbonyl- 4-fluorophenylabsent S-1-acenaphthenyl amino-ethyl)-phenyl 602 S 4-fluorophenyl4-fluorophenyl absent R-1-acenaphthenyl 603 S 3,4-(dimethoxy)-4-fluorophenyl absent R-1-acenaphthenyl phenyl 604 S 4-(methyl)-phenyl4-fluorophenyl absent R-1-acenaphthenyl 605 R 2-(aminoethyl)-phenyl4-fluorophenyl absent S-1-acenaphthenyl 606 S 1-cyclopropyl4-fluorophenyl absent R-1-acenaphthenyl 607 S 1-Adamantanyl4-fluorophenyl CH₂ 3,5-bis- trifluoromethyl-phenyl 608 S 4-pyridyl4-fluorophenyl CH₂ 3,5-bis- trifluoromethyl-phenyl 609 S1-(3-pyridyl)-methyl 4-fluorophenyl CH₂ 3,5-bis- trifluoromethyl-phenyl610 S 3-di(n-butyl)amino-n- 4-fluorophenyl CH₂ 3,5-bis- propyltrifluoromethyl-phenyl 611 R 1-(3-pyridyl)-methyl 4-fluorophenyl absentR-1-acenaphthenyl 612 S 1-(4-pyridyl)-methyl 4-fluorophenyl absentR-1-acenaphthenyl 613 S 1-(3-pyridyl)-methyl 4-fluorophenyl absentR-1-acenaphthenyl 614 S 1-(2-thienyl)-methyl 4-fluorophenyl absentR-1-acenaphthenyl 615 R

4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 616 S H 4-fluorophenyl absentcyclooctyl 617 S 4-pyridinyl 4-fluorophenyl absent cyclooctyl 618 S4-pyridinyl 4-fluorophenyl CH₂

619 S H 4-fluorophenyl CH₂

620 R H 4-fluorophenyl CH₂ cyclooctyl 621 R 4-pyridinyl 4-fluorophenylCH₂ cyclooctyl 622 S

4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 623 R H 4-fluorophenyl absentcyclooctyl 624 R n-butyl 4-fluorophenyl absent cyclooctyl 625 R3-nitrobenzyl 4-fluorophenyl absent cyclooctyl 626 R

4-fluorophenyl absent cyclooctyl 627 R 4-pyridinyl 4-fluorophenyl absentcyclooctyl 628 R 4-methoxycarbonyl- 4-fluorophenyl absent cyclooctylbenzyl 629 R 1-[2-(3H-imidazol-4- 4-fluorophenyl absent cyclooctylyl)-ethyl] 630 —

4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 631 R C(O)O-t-butyl4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 632 R H 4-fluorophenyl CH(CH₃)

633 S dimethylamino-n- 4-fluorophenyl CH₂ cyclooctyl propyl 634 S3-hydroxy-n-propyl 4-fluorophenyl CH₂ cyclooctyl 635 R3-hydroxy-n-propyl 4-fluorophenyl CH₂ cyclooctyl 636 R dimethylamino-n-4-fluorophenyl CH₂ cyclooctyl propyl 637 S 3-hydroxy-n-propyl4-fluorophenyl absent S-1-acenaphthenyl 638 S dimethylamino-n-4-fluorophenyl absent S-1-acenaphthenyl propyl 639 R 3-hydroxy-n-propyl4-fluorophenyl absent S-1-acenaphthenyl 640 R H phenyl absent 1S-(3a-S)-2,3,3a,4,5,6- hexahydro-1H- phenalen-1-yl 641 S 3-methoxy-n-propyl4-fluorophenyl absent R-1-acenaphthenyl 642 S 3-hydroxy-n-propyl4-fluorophenyl absent R-1-acenaphthenyl 643 R 3-hydroxy-n-propyl4-fluorophenyl absent R-1-acenaphthenyl 644 R 3-methoxy-n-propyl4-fluorophenyl absent R-1-acenaphthenyl 645 R

4-fluorophenyl absent R-1-acenaphthenyl 646 S

4-fluorophenyl absent R-1-acenaphthenyl 647 R dimethylamino-n-4-fluorophenyl absent R-1-acenaphthenyl propyl 648 S methyl4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 649 S 3-hydroxy-n-propyl4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 650 S 3-methoxy-n-propyl4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 651 R 3-hydroxy-n-propyl4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 652 R 3-methoxy-n-propyl4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 653 S dimethylamino-n-4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) propyl 654 Smethylamino-n-propyl 4-fluorophenyl absent S-1-acenaphthenyl 655 Smethylamino-n-propyl 4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 656 Rmethylamino-n-propyl 4-fluorophenyl CH₂ 1-(8-methyl-naphthyl) 657 Rmethylamino-n-propyl 4-fluorophenyl CH₂ cyclooctyl 658 Smethylamino-n-propyl phenyl absent 1S-(3a-S)- 2,3,3a,4,5,6-hexahydro-1H- phenalen-1-yl 659 S H phenyl absent 1S-(3a-S)-2,3,3a,4,5,6- hexahydro-1H- phenalen-1-yl 660 R methyl 4-fluorophenylCH₂ 1-(8-methyl-naphthyl) 661 R methylamino-ethyl 4-fluorophenyl CH₂1-(8-methyl-naphthyl) 662 R 1-(4-ethoxycarbonyl- 4-fluorophenyl CH₂1-(8-methyl-naphthyl) piperidinyl) 663 R

4-fluorophenyl absent S-1-acenaphthenyl 664 R methylamino-n-propyl4-fluorophenyl CH₂

665 R t-butoxycarbonyl- 4-fluorophenyl CH₂ 1-(8-methyl-naphthyl)amino-n-propyl 666 R dimethylamino-n- 4-fluorophenyl CH₂1-(8-methyl-naphthyl) propyl 667 R N-methyl-N-t- 4-fluorophenyl CH₂1-(8-methyl-naphthyl) butoxycarbonyl- amino-ethyl

TABLE 2

ID# * R¹ R² R³ (L¹)_(m)

54 S n-butyl benzyl phenyl absent (3a-S)-2,3,3a,4,5,6- hexahydro-1H-phenalen-2-yl 55 S ethyl 4-methyl 4-fluoro- absent 1-acenaphthenylbenzyl phenyl 56 S t-butyl benzyl 4-fluoro- absent 1-acenaphthenylphenyl 57 S ethyl 4-methyl 4-fluoro- absent 4-n-propyl-cyclohexyl benzylphenyl 58 S ethyl 4-methyl 4-fluoro- CH₂CH₂ phenyl benzyl phenyl 59 St-butyl benzyl 4-fluoro- absent 4-n-propyl-cyclohexyl phenyl 60 St-butyl benzyl 4-fluoro- CH₂CH₂ phenyl phenyl 61 Rac ethyl 4-methylphenyl absent 1-acenaphthenyl benzyl 62 Rac t-butyl benzyl phenyl absent1-acenaphthenyl 63 S 2-(dimethyl benzyl 4-fluoro- CH₂ cyclooctylamino)ethyl phenyl 64 S n-butyl benzyl 4-fluoro- CH₂ cyclooctyl phenyl65 S benzyl 2-phenyl- 4-fluoro- CH₂ cyclooctyl ethyl phenyl 78 S

4-methyl benzyl 4-fluoro phenyl CH₂ cyclooctyl 79 S

4-methyl benzyl 4-fluoro phenyl CH₂ cyclooctyl 250 S t-butyl benzyl4-fluoro CH₂ 1-naphthyl phenyl 252 S ethyl 4-methyl 4-fluoro- CH₂1-naphthyl benzyl phenyl 256 S methyl 2-(3,4- 4-fluoro- CH₂ 1-naphthyldimethoxy- phenyl phenyl)ethyl 258 S ethyl 4-methyl 4-fluoro- CH₂2-naphthyl benzyl phenyl 260 S t-butyl benzyl 4-fluoro- CH₂ 2-naphthylphenyl 263 S methyl 2-(3,4- 4-fluoro- CH₂ 2-naphthyl dimethoxy- phenylphenyl)ethyl 264 S ethyl 4-methyl 4-fluoro- CH₂ 4-chlorophenyl benzylphenyl 266 S t-butyl benzyl 4-fluoro- CH₂ 4-chlorophenyl phenyl 270 Smethyl 2-(3,4- 4-fluoro- CH₂ 4-chlorophenyl dimethoxy- phenylphenyl)ethyl 275 S methyl 2-(3,4- 4-fluoro- absent 1-acenaphthenyldimethoxy- phenyl phenyl)ethyl 280 S n-butyl benzyl 4-fluoro- CH₂2,3,4,5,6- phenyl pentamethyl-phenyl 283 S methyl 3-(2-pyridyl)-4-fluoro- CH₂ cyclooctyl n-propyl phenyl 289 S benzyl (1S,2S)-1-4-fluoro- CH₂ cyclooctyl hydroxy- phenyl cyclopent-2- yl-methyl 290 Sbenzyl (1S,2S)-1- 4-fluoro- CH₂ cyclooctyl hydroxy- phenyl cyclohex-2-yl-methyl 291 S benzyl (1S,2S)-1- 4-fluoro- CH₂ cyclooctyl hydroxy-phenyl cyclohept-2- yl-methyl 294 S ethyl 4-methyl 4-fluoro- CH₂5-phenyl-2-thienyl benzyl phenyl 295 Rac methyl 2-(3,4- phenyl absent1-acenaphthenyl dimethoxy- phenyl)ethyl 299 R t-butyl benzyl 4-fluoro-absent 1-acenaphthenyl phenyl 305 R methyl 2-(3,4- 4-fluoro- absent1-acenaphthenyl dimethoxy- phenyl phenyl)ethyl 313 S benzyl2-phenylethyl 4-fluoro- absent 1-acenaphthenyl phenyl 339 R methyl2-(3,4- 4-fluoro- absent R-1-acenaphthenyl dimethoxy- phenylphenyl)ethyl 340 R methyl 2-(3,4- 4-fluoro- absent S-1-acenaphthenyldimethoxy- phenyl phenyl)ethyl 362 S benzyl benzyl 4-fluoro- absent1-acenaphthenyl phenyl 364 S methyl 2-(2-pyridyl) 4-fluoro- absent1-acenaphthenyl ethyl phenyl 389 R t-butyl benzyl 4-fluoro- CH₂1-(8-methyl-naphthyl) phenyl 391 R methyl 2-(3,4- 4-fluoro- CH₂1-(8-methyl-naphthyl) dimethoxy- phenyl phenyl)ethyl 394 S ethyl4-methyl 4-fluoro- CH₂ 1-(8-methyl-naphthyl) benzyl phenyl 395 S t-butylbenzyl 4-fluoro- CH₂ 1-(8-methyl-naphthyl) phenyl 399 S methyl 2-(3,4-4-fluoro- CH₂ 1-(8-methyl-naphthyl) dimethoxy- phenyl phenyl)ethyl 423 Rmethyl methyl 4-fluoro- absent R-1-acenaphthenyl phenyl 428 R methylmethyl 4-fluoro- absent S-1-acenaphthenyl phenyl 429 R methyl ethyl4-fluoro- absent S-1-acenaphthenyl phenyl 432 S methyl methyl 4-fluoro-absent S-1-acenaphthenyl phenyl 433 S methyl ethyl 4-fluoro- absentS-1-acenaphthenyl phenyl 434 R methyl ethyl 4-fluoro- absentR-1-acenaphthenyl phenyl 435 S methyl methyl 4-fluoro- absentR-1-acenaphthenyl phenyl 436 S methyl ethyl 4-fluoro- absentR-1-acenaphthenyl phenyl 439 S methyl methyl 4-fluoro- CH₂1-(8-methyl-naphthyl) phenyl 440 S methyl ethyl 4-fluoro- CH₂1-(8-methyl-naphthyl) phenyl 441 R methyl methyl 4-fluoro- CH₂1-(8-methyl-naphthyl) phenyl 442 R methyl ethyl 4-fluoro- CH₂1-(8-methyl-naphthyl) phenyl 455 S 4-methyl- 6-methylthio- 4-fluoro- CH₂cyclooctyl benzyl 2-pyridyl- phenyl carbonyl 456 S n-butyl benzyl4-fluoro- CH₂ 2-trifluoromethyl-6- phenyl chloro-phenyl 457 S methyl2-(3,4- 4-fluoro- CH₂ 2-trifluoromethyl-6- dimethoxy- phenylchloro-phenyl phenyl)ethyl 459 S benzyl 2-(dimethyl- 4-fluoro- CH₂2-trifluoromethyl-6- amino)ethyl phenyl chloro-phenyl 462 R ethyl4-methyl- 4-fluoro- absent 1-acenaphthenyl benzyl phenyl 668 S ethylphenyl 4-fluoro- absent R-1-acenaphthenyl phenyl 669 S methyl phenyl4-fluoro- absent R-1-acenaphthenyl phenyl 670 S ethoxy- benzyl 4-fluoro-CH₂ 3,5-bis- carbonyl- phenyl trifluoromethyl-phenyl methyl 671 Sn-butyl benzyl 4-fluoro- CH₂ 3,5-bis- phenyl trifluoromethyl-phenyl 672S 1-phenyl- benzyl 4-fluoro- CH₂ 3,5-bis- ethyl phenyltrifluoromethyl-phenyl 673 S 2-(3,4- methyl 4-fluoro- CH₂ 3,5-bis-dimethoxy- phenyl trifluoromethyl-phenyl phenyl)- ethyl 674 S (dimethyl-benzyl 4-fluoro- CH₂ 3,5-bis- amino)- phenyl trifluoromethyl-phenylethyl 675 S 2-(3,4- methyl 4-fluoro- absent cyclooctyl dimethoxy- phenylphenyl)- ethyl 676 S benzyl n-butyl 4-fluoro- absent cyclooctyl phenyl677 S benzyl n-butyl 4-fluoro- phenyl CH₂

678 R 2-(3,4- methyl 4-fluoro- CH₂ cyclooctyl dimethoxy- phenyl phenyl)-ethyl 679 S t-butoxy- methyl 4-fluoro- absent R-1-acenaphthenyl carbonylphenyl 680 S t-butoxy- methyl 4-fluoro- CH₂ 1-(8-methyl-naphthyl)carbonyl phenyl 681 R amino-n- methyl 4-fluoro- CH₂1-(8-methyl-naphthyl) propyl phenyl

TABLE 3

ID# * T¹ (NR¹R² taken together)

66 S 1-(4-(3-trifluoromethyl-phenyl)- cyclooctyl-methyl piperazinyl) 67S 1-(4-piperidinyl-piperidinyl) cyclooctyl-methyl 68 S1-(4-(3,4-methylenedioxyphenyl- cyclooctyl-methyl methyl)-piperazinyl)69 S 1-(3-(diethylaminocarbonyl)- cyclooctyl-methyl piperidinyl) 70 S1-(2,3-dihydro-1H-pyrrolyl) cyclooctyl-methyl 71 S1-(4-[(4-chlorophenyl)-phenylmethyl]- cyclooctyl-methyl piperazinyl) 72S 2-(1,2,3,4-tetrahydro-isoquinolinyl) cyclooctyl-methyl 73 S1-(4-t-butoxycarbonyl-piperazinyl) cyclooctyl-methyl 74 S2-(1,2,3,4-tetrahydro-6,7-dimethoxy- cyclooctyl-methyl isoquinolinyl) 75S 4-(2,6-dimethyl-morpholinyl) cyclooctyl-methyl 76 S1-(4-benzyl-piperazinyl) cyclooctyl-methyl 115 S2-(1,2,3,4-tetrahydro-isoquinolinyl) 2-(2-(2-thienyl)- phenyl)ethyl 160R 1-(4-t-butoxycarbonyl-piperazinyl) 2-(2-(2-thienyl)- phenyl)ethyl 165S 1-(4-t-butoxycarbonyl-piperazinyl) 2-(2-(2-thienyl)- phenyl)-ethyl 166S 2-(1,2,3,4-tetrahydro-6,7-dimethoxy- 2-(2-(2-thienyl)- isoquinolinyl)phenyl)ethyl 181 R 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-(2-(2-thienyl)- isoquinolinyl) phenyl)ethyl 183 R 1-pyrrolidinyl2-(2-(2-thienyl)- phenyl)ethyl 188 R 1-(4-ethoxycarbonyl-piperidinyl)2-(2-(2-thienyl)- phenyl)-ethyl 257 S2-(1,2,3,4-tetrahydro-6,7-dimethoxy- 2-(2-(2-thienyl)- isoquinolinyl)phenyl)ethyl 284 S 1-(2S-(phenylamino-methyl)- cyclooctyl-methylpyrrolidinyl) 682 S 2-(1,2,3,4-tetrahydro-isoquinolinyl)3,5-bis-trifluoro- methyl-benzyl 683 S 1-[4-(3-trifluoromethyl-phenyl)-3,5-bis-trifluoro- piperazinyl] methyl-benzyl 684 S1-(4-ethoxycarbonyl-piperidinyl) 3,5-bis-trifluoro- methyl-benzyl 685 S1-(2,3-dihydro-pyrrolidinyl) 3,5-bis-trifluoro- methyl-benzyl 686 S3-(diethylaminocarbonyl)-piperidinyl 3,5-bis-trifluoro- methyl-benzyl687 S

cyclooctyl 688 R 1-(3,4-dihydroxy-2,5-bis- cyclooctylhydroxymethyl-pyrrolidinyl) 689 R 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-cyclooctyl isoquinolinyl) 690 R

cyclooctyl

TABLE 4

ID# * T² (NR¹R² taken together)

296 R 2-(1,2,3,4-tetrahydro-6,7-dimethoxy- 1-acenaphthenylisoquinolinyl) 332 S 1-(4-benzyl-piperazinyl) 1-acenaphthenyl 333 S1-(4-(3-trifluoromethyl-phenyl)- 1-acenaphthenyl piperazinyl) 334 S1-(4-(1-piperidinyl)-piperidinyl) 1-acenaphthenyl 335 S1-(4-(3,4-methylenedioxyphenyl- 1-acenaphthenyl methyl)-piperazinyl) 336S 1-(3-(diethylaminocarbonyl)- 1-acenaphthenyl piperidinyl) 337 S1-(4-[(4-chlorophenyl)-phenyl- 1-acenaphthenyl methyl]-piperazinyl) 360S 1-(4-ethoxycarbonyl-piperidinyl) 1-acenaphthenyl 377 S2-(1,2,3,4-tetrahydro-6,7-dimethoxy- 1-acenaphthenyl isoquinolinyl) 382R 1-imidazolyl 1-acenaphthenyl 388 S2-(1,2,3,4-tetrahydro-6,7-dimethoxy- 1-(8-methyl-naphthyl)isoquinolinyl) 445 R 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-acenaphthenyl isoquinolinyl) 465 S 1-piperidinyl R-1-acenaphthenyl 691S 1-morpholinyl R-1-acenaphthenyl 692 S 1-pyrrolidinyl R-1-acenaphthenyl693 R 1-(4-ethoxycarbonyl-piperidinyl) R-1-acenaphthenyl 694 R1-(4-phenyl-piperidinyl) R-1-acenaphthenyl 695 R1-(3-hydroxymethyl-piperidinyl) R-1-acenaphthenyl 696 R1-(3-ethoxycarbonyl-piperidinyl) R-1-acenaphthenyl 697 R 1-piperidinylR-1-acenaphthenyl 698 R 1-pyrrolidinyl R-1-acenaphthenyl 699 S1-(3,5-dimethyl-piperidinyl) R-1-acenaphthenyl 700 S1-(4-phenyl-piperidinyl) R-1-acenaphthenyl 701 S1-(4-ethoxycarbonyl-piperidinyl) R-1-acenaphthenyl 702 S1-(3-hydroxymethyl-piperidinyl) R-1-acenaphthenyl 703 R1-(3,5-dimethyl-piperidinyl) R-1-acenaphthenyl 704 S 1-pyrrolidinyl1-(8-methyl-naphthyl) 705 R 1-pyrrolidinyl 1-(8-methyl-naphthyl) 706 R1-(3-(R)-hydroxy-pyrrolidinyl) 1-(8-methyl-naphthyl) 707 R1-(3-hydroxy-piperidinyl) 1-(8-methyl-naphthyl) 708 R1-(3-(R)-dimethylamino-pyrrolidinyl) 1-(8-methyl-naphthyl) 709 R1-(4-hydroxy-piperidinyl) 1-(8-methyl-naphthyl) 710 R1-(3-(R)-t-butoxycarbonylamino- 1-(8-methyl-naphthyl) pyrrolidinyl) 711R 1-(4-t-butoxycarbonylamino- 1-(8-methyl-naphthyl) piperidinyl) 712 R1-(3-hydroxy-pyrrolidinyl) 1-(8-methyl-naphthyl) 713 R1-(4-pyrrolidinyl-piperidinyl) 1-(8-methyl-naphthyl) 714 R1-(3-(S)-hydroxy-pyrrolidinyl) 1-(8-methyl-naphthyl) 715 R1-((3-(S)-ethylamino)pyrrolidinyl) 1-(8-methyl-naphthyl) 716 R1-(3-(R)-amino-pyrrolidinyl) 1-(8-methyl-naphthyl) 717 R1-(3-(S)-amino-pyrrolidinyl) 1-(8-methyl-naphthyl) 718 R1-(4-dimethylamino-piperidinyl) 1-(8-methyl-naphthyl) 719 R1-(3-(R)-methylamino-pyrrolidinyl) 1-(8-methyl-naphthyl) 720 R1-(3-(S)-methylamino-pyrrolidinyl) 1-(8-methyl-naphthyl) 721 R1-(3-(N-methyl-N-t-butoxycarbonyl- 1-(8-methyl-naphthyl)amino)-pyrrolidinyl)

TABLE 5

ID# * R³ (L¹)_(m)

100 R 4-fluorophenyl CH₂ cyclooctyl 101 S 4-fluorophenyl absent1-acenaphthenyl 102 R 4-fluorophenyl CH₂CH₂ phenyl 103 R 4-fluorophenylabsent 4-n-propyl-cyclohexyl 104 Rac phenyl absent 1-acenaphthenyl 179 Rphenyl CH₂CH₂ 2-(2-thienyl)-phenyl 447 R 4-fluorophenyl CH₂ cyclooctyl

TABLE 6

ID# * X R³ (L¹)_(m)

105 R 2-(3,4-dimethoxy 4-fluoro CH₂ cyclooctyl phenyl)-ethyloxy phenyl106 R 2-(3,4-dimethoxy phenyl CH₂CH₂ 2-(2-thienyl)-phenylphenyl)-ethyloxy 107 R 3-methylphenylthio phenyl CH₂CH₂2-(2-thienyl)-phenyl 108 R 3-methylphenylthio 4-fluoro CH₂ cyclooctylphenyl 178 S

phenyl CH₂CH₂ 2-(2-thienyl)-phenyl 460 R

4-fluoro phenyl CH₂ cyclooctyl

TABLE 7

ID No. * R¹ R² 110 Rac H 3-(4-morpholinyl)-n-propyl 111 S H3-(4-morpholinyl)-n-propyl 112 R H 3-(4-morpholinyl)-n-propyl 113 S H3-chlorobenzyl 114 S H 2-ethoxybenzyl 116 S H(2,5-dimethoxy-2,5-dihydro-fur-2-yl)- methyl 117 S n-butyl benzyl 118 SH 2,5-difluorobenzyl 119 S H 2-phenyl-ethyl 120 S H 2-(5-bromo-pyridyl)121 S H 3-iodobenzyl 122 5 H 2,2,2-trifluoroethyl 123 5 H 3-nitrobenzyl124 S H 3,4-difluorobenzyl 125 S H 3-bromobenzyl 126 S H 4-chlorobenzyl127 S H 4-methoxybenzyl 128 S H 3,4,5-trimethoxybenzyl 129 S H2-(2-thienyl)ethyl 130 S H 3-methylbenzyl 131 S H 2-methoxybenzyl 132 SH benzyl 133 S H 4-bromobenzyl 134 S H 3,5-di(trifluoromethyl) benzyl135 S H 2-(3-methoxyphenyl)ethyl 136 S benzyl 2-phenylethyl 137 R H2-bromobenzyl 138 R H 2-(4-bromophenyl)ethyl 139 R H4-(N,N-dimethylamino) benzyl 140 R H 4-methylbenzyl 141 R H2-methylbenzyl 142 R H 2-(6-fluoro-2-indolyl)ethyl 143 R H3-fluorobenzyl 144 R H 3-methoxybenzyl 145 R H 2-(4-methoxyphenyl)ethyl146 R H 2-trifluoromethylbenzyl 147 R H 2-(4-imidazolyl)ethyl 148 R H3,5-dimethoxybenzyl 149 R H t-butyl 150 R H 2-pyridyl-methyl 151 R H2-(3,4-dimethoxyphenyl) ethyl 152 R H 2-fluorobenzyl 153 R H3-trifluoromethylbenzyl 154 R H 4-pyridyl 155 R H4-trifluoromethoxybenzyl 156 R H 2-phenyloxy-ethyl 157 R H1-naphthyl-methyl 158 R H 4-fluorobenzyl 159 R H 4-trifluoromethylbenzyl161 R H 4-pyridyl-methyl 162 R H 2,4-dichlorobenzyl 163 S H

164 S benzyl benzyl 167 S H 1-(3,4-methylene dioxyphenyl)methyl 168 Sbenzyl ethoxycarbonylmethyl 169 S H 2-phenyl-cyclopropyl 170 S H4-methoxycarbonylbenzyl 171 S benzyl 2-(N,N-dimethylamino)ethyl 173 Smethyl benzyl 174 S ethyl benzyl 175 R benzyl carboxymethyl 176 R benzyl2-(N,N-dimethylamino)ethyl 177 R n-butyl benzyl 180 R H2-phenyl-cyclopropyl 182 R H 4-methoxycarbonylbenzyl 187 R H2-(2,5-dimethoxy-2,5-dihydro-fur-2- yl)-methyl 189 R H2,4-dimethoxybenzyl 190 R H 4-biphenyl 191 R benzyl ethoxycarbonylmethyl192 R H 4-methoxybenzyl 193 S H 2-methylbenzyl 194 S H3,5-dimethoxybenzyl 197 S H 4-pyridyl 198 S H 2,4-dichlorobenzyl 203 S H3,4-dimethoxybenzyl 204 R H 4-bromobenzyl 205 R H 3-methylbenzyl 206 R H2-(2-thienyl)-ethyl 208 S H 3-nitrobenzyl 209 S H 2-bromobenzyl 210 S H2-(4-imidazolyl)-ethyl 211 S H 2-(phenoxy)-ethyl 215 S H2,3-dimethoxybenzyl 216 S H

217 S H adamantanyl 218 S H n-propyl 219 S n-propyl n-propyl 220 Sbenzyl benzyl 224 S H 3-methoxybenzyl 225 S H 3-pyridyl-methyl 227 S H2,4-difluorobenzyl 228 R H 2-methoxybenzyl 229 S H 3-(phenyl)-n-propyl230 S benzyl 2-phenylethyl

TABLE 8

ID # * R² R³ (L¹)_(m)

722 S H 4-fluorophenyl absent R-1-acenaphthenyl

Representative intermediates in the preparation of the compounds of thepresent invention are as listed in Tables 9 and 10. Wherein Table 9, Ais listed as oxarinyl-methyl with no indication of thestereo-configuration, the oxarinyl-methyl group was present as racemate.

TABLE 9

          ID #           A           R³           (L¹)_(m)

500 H 4-fluorophenyl absent 1-acenaphthenyl 501 H 4-fluorophenylCH₂—CH(CH₃)—CH₂ phenyl 502 H 4-fluorophenyl CH₂CH₃ 503 H 4-fluorophenylCH₂CH₂ phenyl 504 H 4-fluorophenyl absent 4-n-propyl- cyclohexyl 505 H4-fluorophenyl C(O)O-t-butyl 506 H 4-fluorophenyl CH₂ 2-naphthyl 507 H4-fluorophenyl CH₂ 1-naphthyl 508 H 4-fluorophenyl CH₂ 4-chlorophenyl521 H 4-fluorophenyl CH₂ 4-quinolinyl 522 H 4-fluorophenyl CH₂8-quinolinyl 544 H 4-fluorophenyl absent 1,3,4-trihydro-2- naphthyl 546H 4-fluorophenyl CH₂ 5-phenyl-2-thienyl 547 H 4-fluorophenyl CH₂1-(8-methyl- naphthyl) 548 H 4-fluorophenyl CH₂ 1-(4-methyl- naphthyl)549 H 4-fluorophenyl absent 2-hydroxy- cycloheptyl 551 H 4-fluorophenylCH₂ 1-(2-methyl- naphthyl) 555 H 4-fluorophenyl absent R-1-acenaphthenyl556 H 4-fluorophenyl absent S-1-acenaphthenyl 509 oxiranyl- phenylabsent 1-acenaphthenyl methyl 510 R-oxiranyl- 4-fluorophenyl absent4-n-propyl- methyl cyclohexyl 511 R-oxiranyl- 4-fluorophenyl CH₂CH₂phenyl methyl 512 oxiranyl- 4-fluorophenyl absent 1-acenaphthenyl methyl513 R-oxiranyl- 4-fluorophenyl CH₂ 4-chlorophenyl methyl 514 R-oxiranyl-4-fluorophenyl CH₂ 1-naphthyl methyl 516 R-oxiranyl- 4-fluorophenylC(O)O-t-butyl absent methyl 517 S-oxiranyl- 4-fluorophenyl C(O)O-t-butylabsent methyl 518 oxiranyl- phenyl CH₂CH₂ 2-(2-thienyl) phenyl methyl519 S-oxiranyl- phenyl CH₂CH₂ 2-(2-thienyl) phenyl methyl 520R-oxiranyl- phenyl CH₂CH₂ 2-(2-thienyl) phenyl methyl 540 R-oxiranyl-4-fluorophenyl CH₂ cyclooctyl methyl 541 R-oxiranyl- 4-fluorophenyl CH₂5-phenyl-2-thienyl methyl 542 S-oxiranyl- 4-fluorophenyl CH₂ 2-naphthylmethyl 543 S-oxiranyl- 4-fluorophenyl CH₂CH₃ absent methyl 550S-oxiranyl- 4-fluorophenyl CH₂ 1-(8-methyl- methyl naphthyl) 552 methoxy4-fluorophenyl CH₂ 1-(8-methyl- carbonyl- naphthyl) methyl 553R-oxiranyl- 4-fluorophenyl CH₂ 1-(8-methyl- methyl naphthyl) 554 R-2,3-4-fluorophenyl CH₂ 1-(8-methyl- dihydroxy- naphthyl) n-propyl 564S-oxiranyl- 4-fluorophenyl absent R-1-acenaphthenyl methyl 565R-oxiranyl- 4-fluorophenyl absent R-1-acenaphthenyl methyl 566S-oxiranyl- 4-fluorophenyl absent S-1-acenaphthenyl methyl 567R-oxiranyl- 4-fluorophenyl absent S-1-acenaphthenyl methyl 568 2R-4-fluorophenyl absent 1-acenaphthenyl hydroxy-3- ethoxy-n- propyl 5692R- 4-fluorophenyl absent S-1-acenaphthenyl hydroxy-3- ethoxy-n- propyl570 2S- 4-fluorophenyl absent R-1-acenaphthenyl hydroxy-3- ethoxy-n-propyl 571 2R- 4-fluorophenyl absent R-1-acenaphthenyl hydroxy-3-ethoxy-n- propyl 572 H 4-fluorophenyl CH₂

573 H 4-fluorophenyl CH₂ 3-(2H)-chromenyl 576 oxiranyl- phenyl absent1-acenaphthenyl methyl 578 R-oxiranyl- 4-fluorophenyl CH₂2-trifluoromethyl-6- methyl chloro-phenyl 579 3-chloro- 4-fluorophenylabsent R-1-acenaphthenyl 2S- hydroxy-n- propyl 580 S-oxiranyl-4-fluorophenyl CH₂ cyclooctyl methyl 581 H phenyl CH₂CH₂2-(2-thienyl)-phenyl 582 H 4-fluorophenyl CH₂ cyclooctyl 583 H4-fluorophenyl CH₂ 2,3,4,5,6- pentamethyl-phenyl 584 R-oxiranyl-4-fluorophenyl CH₂ 2,3,4,5,6- methyl pentamethyl-phenyl 723 R-oxiranyl-4-fluorophenyl absent R-1-acenaphthenyl ethyl 725 R-oxiranyl-4-fluorophenyl CH₂ 2,3,4,5,6- methyl pentamethylphenyl 726 H4-fluorophenyl CH₂

727 R-oxiranyl- methyl 4-fluorophenyl CH₂

728 H 4-fluorophenyl CH₂ 1-(8-methyl-1,2,3,4- tetrahydro-naphthyl) 729 H4-fluorophenyl CH(CH₃)

730 H 4-fluorophenyl absent

731 S-oxiranyl- 4-fluorophenyl absent cyclooctyl methyl 732 H4-fluorophenyl CH₂

733 H 4-fluorophenyl CH₂ 1-[8-methoxy)- naphthyl] 734 H 4-fluorophenylCH₂ 1-[8- hydroxymethyl)- naphthyl] 735 H 4-fluorophenyl absentcyclooctyl

TABLE 10

ID # * R¹ R² W 523 R ethyl 4-methylbenzyl H 524 R H2-(4-morpholinyl)-ethyl H 525 R t-butyl benzyl H 526 R H2-(3,4-dimethoxy-phenyl)-ethyl H 527 R H 2-(3,4-methylenedioxy phenyl)-H ethyl 528 R H 2-(2-nitro-4,5-dimethoxy-phenyl)- H ethyl 529 S ethyl4-methylbenzyl H 530 S H 2-(4-morpholinyl)-ethyl H 531 S t-butyl benzylH 532 S H 2-(3,4-dimethoxy-phenyl)-ethyl H 533 S H 2-(3,4-methylenedioxyphenyl)- H ethyl 534 S H 2-(2-nitro-4,5-dimethoxy-phenyl)- H ethyl 535 Sethyl 4-methylbenzyl t- butoxycarbonyl 536 R ethyl 4-methylbenzyl ethyl537 R H 2-(4-morpholinyl)-ethyl ethyl 538 R t-butyl benzyl ethyl 539 R H2-(3,4-dimethoxy-phenyl)-ethyl ethyl

Molecular weights for representative compounds of the present inventionexemplified in Tables 1-10 above were measured using a MicromassPlatform LC-Electrospray Mass Spectrometer, Chemical IonizationSpectrometer HP5989A or Agilent LC/MSD Electrospray Mass Spectrometerwith results as listed in Table 11.

TABLE 11 ID# Theor. MW M/e[MH+] 1 559.77 560.8 2 596.78 597.7 3 672.73673.6 4 540.72 541.7 5 615.63 617.9 6 610.81 611.8 7 572.71 573.3 8596.78 597.5 9 598.8 599.5 10 580.78 581.5 11 550.76 551.5 12 572.71573.5 13 602.60 604.3 14 566.76 567.5 15 615.60 617.4 16 672.73 673.5 17594.85 595.5 18 550.76 551.5 19 588.76 589.5 20 615.63 617.4 21 571.18571.5 22 596.78 597.5 23 581.73 582.5 24 537.72 538.4 25 596.78 597.2 26556.79 557.4 27 550.76 552.4 28 540.72 541.5 29 604.73 605.5 30 629.65630.5 31 605.62 607.3 32 537.72 538.4 33 604.73 605.4 34 566.76 567.5 35566.76 567.7 36 523.69 523.9 38 610.81 611.5 39 537.72 538.5 40 586.79587.4 41 550.76 551.4 42 551.75 551.5 43 626.81 627.4 44 615.63 616.4 45596.78 597.3 46 605.62 607.4 47 587.70 588.3 48 638.70 639.3 49 610.81611.4 50 539.63 540.3 51 590.74 591.3 52 621.00 622.0 53 569.00 570.0 54620.88 621.5 55 606.70 607.3 56 620.80 621.3 57 578.81 579.5 58 558.74559.3 59 592.84 593.4 60 572.77 573.3 61 588.00 589.0 62 602.00 603.0 63607.28 608.3 64 592.84 593.5 65 640.88 641.5 66 659.81 660.1 67 597.86598.2 68 649.85 650.1 69 613.86 614.3 70 498.68 499.5 71 716.38 717.4 72562.77 563.5 73 615.83 616.4 74 622.82 623.2 75 544.75 545.4 76 605.84606.2 78 649.89 650.2 79 750.01 751.5 100 592.77 593.8 101 620.70 621.3102 572.70 573.3 103 592.77 593.3 104 602.70 603.0 105 611.79 612.4 106655.86 656.4 107 597.84 598.4 108 553.78 554.6 110 617.85 618.3 111617.85 618.3 112 617.85 618.3 113 615.24 615.3 114 624.85 625.3 115606.83 607.3 116 632.82 633.3 117 636.90 637.4 118 616.78 617.3 119594.80 595.3 120 646.65 648.2 121 706.68 707.2 122 572.69 573.3 123625.79 626.3 124 616.77 617.3 125 659.68 661.2 126 615.30 615.3 127610.82 611.3 128 670.87 671.3 129 600.85 601.2 130 594.82 595.3 131610.82 611.3 132 580.79 581.2 133 659.69 661.2 134 716.79 717.2 135624.85 625.3 136 684.94 685.3 137 659.69 661.2 138 673.72 675.3 139623.86 624.4 140 594.82 595.4 141 594.82 595.4 142 651.85 652.3 143598.78 599.3 144 610.82 611.3 145 624.85 625.3 146 648.80 649.3 147584.76 585.3 148 640.85 641.3 149 546.77 547.3 150 581.78 582.3 151654.87 655.5 152 598.78 599.3 153 648.79 649.3 154 567.75 568.3 155664.79 665.3 156 610.82 611.3 157 630.85 631.3 158 598.78 599.3 159648.80 649.3 160 659.89 660.4 161 581.78 582.3 162 649.68 651.1 163759.11 759.1 164 670.82 671.4 165 659.89 660.5 166 666.88 667.4 167624.80 625.4 168 666.88 667.4 169 606.83 607.5 170 638.83 639.4 171651.92 653.0 173 594.80 595.8 174 608.85 609.9 175 638.83 639.6 176651.92 652.9 177 636.90 637.6 178 694.91 695.8 179 636.90 637.6 180606.83 607.9 181 666.88 667.8 182 638.83 639.8 183 544.76 545.7 187632.82 633.9 188 630.85 631.9 189 640.85 641.9 190 642.86 643.8 191666.88 667.8 192 610.82 611.9 193 594.82 595.8 194 640.85 641.9 197567.75 568.8 198 649.68 651.6 203 640.85 641.7 204 659.69 662.0 205594.82 595.9 206 600.85 601.7 208 625.79 626.8 209 659.69 661.2 210584.79 585.8 211 610.82 611.8 215 640.85 641.7 216 759.11 759.7 217638.92 639.8 218 532.75 533.6 219 574.83 575.9 220 670.92 671.7 224610.82 611.8 225 581.78 582.7 227 616.78 617.7 228 610.82 611.8 229608.85 609.7 230 684.94 685.7 250 608.79 609.3 251 575.72 576.3 252594.76 595.3 253 626.76 627.3 254 610.72 611.2 255 671.76 672.3 256640.79 641.4 257 638.77 639.3 258 594.76 595.3 259 575.72 576.3 260608.79 609.3 261 626.76 627.3 262 610.72 611.2 263 640.78 641.4 264579.15 579.3 265 560.10 560.2 266 593.17 593.3 267 611.15 691.2 268595.10 595.2 269 656.14 656.2 270 625.17 625.3 271 622.72 623.2 275652.80 653.4 276 683.79 684.3 279 650.88 651.3 280 628.88 629.2 281566.77 567.5 282 743.95 744.1 283 565.75 566.4 284 605.85 605.9 285604.86 605.3 289 634.89 635.3 290 648.91 649.2 291 662.94 663.3 292658.84 659.2 293 607.80 608.3 294 626.84 627.3 295 634.82 635.4 296650.80 651.3 298 587.74 588.3 299 620.82 621.4 300 638.79 639.3 305652.82 653.3 307 624.76 625.3 308 609.71 610.3 309 619.79 620.3 310626.78 627.3 311 554.67 555.4 312 690.61 691.2 313 668.86 669.3 314600.69 601.3 315 643.61 643.6 316 599.15 599.2 317 594.74 595.3 318594.74 595.3 319 700.71 701.2 320 654.79 655.3 321 582.70 583.3 322594.74 595.3 323 608.76 609.3 324 624.76 625.3 325 578.74 579.3 326592.76 593.4 327 551.67 552.3 328 648.71 649.3 329 594.74 595.3 330578.74 579.0 331 624.76 625.3 332 633.82 634.3 333 687.79 688.3 334625.84 626.4 335 677.83 678.3 336 641.84 642.5 337 744.36 744.3 338643.90 644.4 339 652.82 653.4 340 652.82 653.4 341 578.74 579.3 342600.69 601.3 343 633.60 633.2 344 632.71 634.0 345 564.71 565.3 346582.70 583.3 347 632.71 634.0 348 622.75 623.2 349 624.76 625.3 350599.15 599.2 351 608.76 609.3 352 643.10 643.2 353 578.74 579.3 354584.72 583.3 355 643.61 645.2 356 608.72 609.0 358 600.69 601.0 360614.77 615.0 362 654.84 655.3 364 593.75 594.2 365 657.63 659.2 366565.70 566.2 367 654.79 655.3 368 633.60 635.2 370 609.71 610.3 371614.77 615.3 372 584.76 595.3 373 632.71 633.3 374 743.03 743.6 375579.72 580.3 376 565.70 566.2 377 650.80 651.3 378 551.67 552.2 379551.67 552.2 380 581.70 582.2 381 551.67 552.3 382 525.63 526.2 383565.70 566.2 385 640.81 641.4 386 640.81 641.4 387 589.76 590.4 388652.82 653.4 389 622.83 623.4 390 624.76 625.3 391 654.83 655.3 392596.75 597.3 393 553.69 554.2 394 608.81 609.4 395 622.83 623.4 396589.76 590.4 398 596.75 597.3 399 654.83 655.3 418 624.76 625.3 419551.67 552.3 420 474.58 475.2 421 551.67 552.3 422 476.6 477.3 423502.64 503.3 424 474.58 475.2 425 488.61 489.3 426 474.58 475.2 427488.61 489.3 428 502.64 503.3 429 516.66 517.3 430 474.58 475.2 431488.61 489.3 432 502.64 503.3 433 516.66 517.3 434 516.66 517.3 435502.64 503.3 436 516.66 517.3 437 488.61 489.3 438 476.6 477.3 439504.65 505.4 440 518.68 519.3 441 504.65 505.4 442 518.68 519.3 443504.61 505.2 444 518.64 519.3 445 650.80 651.3 446 622.75 623.2 447592.78 593.4 448 594.74 595.3 451 743.95 744.1 452 580.75 581.5 453446.61 447.9 454 502.72 503.2 455 701.95 702.0 456 661.19 662.5 457693.19 694.0 458 591.05 592.0 459 676.20 677.4 460 564.77 565.2 461683.79 684.3 462 606.79 607.3 463 580.71 581.3 464 593.75 594.3 465542.70 543.3 500 401.49 402.2 501 367.47 368.2 502 277.34 278.2 503353.44 354.2 504 373.52 374.2 505 349.41 372.0 506 389.48 390.1 507389.48 390.1 508 373.86 374.1 509 439.56 440.2 510 409.51 410.2 511429.58 430.3 512 457.55 458.3 513 429.93 430.2 514 445.54 446.3 516405.47 428.3 517 405.47 428.3 518 473.65 474.1 519 473.65 474.1 520473.65 474.1 521 390.45 391.2 522 390.45 391.0 523 454.58 455.0 524435.54 436.0 525 468.61 469.0 526 486.58 487.0 527 470.54 471.0 528531.58 532.0 529 454.48 544.0 530 435.54 436.0 531 468.61 469.0 532486.58 488.0 533 470.54 471.0 534 531.58 532.0 535 554.70 555.3 536482.65 483.3 537 463.60 464.3 538 496.67 497.4 539 514.65 515.2 540429.58 430.5 541 477.61 478.2 542 445.54 446.3 543 333.41 334.2 544379.48 380.2 546 421.54 422.1 547 403.50 404.2 548 403.50 404.2 549361.46 362.3 550 459.57 460.2 551 403.50 404.2 552 475.57 476.2 553459.57 460.2 554 477.58 478.2 555 401.49 402.1 556 401.49 402.1 564457.55 458.3 565 457.55 458.3 566 457.55 458.3 567 457.55 548.3 568503.62 504.3 569 503.62 504.3 570 503.62 504.3 571 503.62 504.3 572411.48 412.2 573 393.47 394.2 576 439.56 458.3 578 497.92 498.9 579494.01 494.2 581 417.58 418.1 582 373.52 374.1 583 409.55 410.5 584465.62 466.1 600 550.68 551.7 601 693.87 694.9 602 568.67 569.7 603610.74 611.7 604 564.71 565.7 605 593.75 594.8 606 514.65 515.7 607696.76 697.8 608 625.59 626.6 609 639.62 640.6 610 717.82 718.8 611565.7 566.7 612 565.7 566.7 613 565.7 566.7 614 570.73 571.7 615 692.76693.8 616 432.59 433.6 617 509.67 510.7 618 533.7 534.7 619 456.61 457.6620 446.61 447.6 621 523.7 524.7 622 692.76 693.8 623 432.59 433.6 624488.69 489.7 625 567.71 568.7 626 701.03 702.0 627 509.67 510.7 628580.75 581.8 629 526.7 527.7 630 658.86 659.9 631 576.72 577.7 632496.65 497.7 633 531.76 532.8 634 504.69 505.7 635 504.69 505.7 636531.76 532.8 637 532.66 533.7 638 559.73 560.7 639 532.73 533.7 640474.65 475.7 641 546.69 547.7 642 532.66 533.7 643 532.66 533.7 644546.69 547.7 645 690.74 691.7 646 690.74 691.7 647 559.73 560.7 648490.63 491.6 649 534.68 535.7 650 548.71 549.7 651 534.68 535.7 652235.13 236.1 653 430.5 431.5 654 545.71 546.7 655 547.72 548.7 656547.72 548.7 657 517.74 518.7 658 545.77 546.8 659 474.65 475.7 660490.63 491.6 661 533.7 534.7 662 631.8 632.8 663 578.74 579.7 664 529.75530.8 665 633.81 634.8 666 561.75 562.8 667 633.80 634.2 668 578.74579.7 669 564.71 565.7 670 724.73 725.7 671 694.74 695.7 672 742.79743.8 673 726.74 727.7 674 709.76 710.8 675 610.82 611.8 676 578.82579.8 677 602.84 603.8 678 564.74 565.7 679 645.82 646.8 680 647.84648.8 681 547.72 548.7 682 664.67 665.7 683 761.71 762.7 684 688.69689.7 685 600.58 601.6 686 715.76 716.8 687 688.66 689.7 688 578.73579.7 689 608.8 609.8 690 702.36 703.4 691 544.68 545.7 692 528.68 529.7693 614.77 615.8 694 618.8 619.8 695 572.73 573.7 696 614.77 615.8 697542.7 543.7 698 528.68 529.7 699 570.76 571.8 700 618.8 619.8 701 614.77615.8 702 572.73 573.7 703 570.76 571.8 704 530.69 531.7 705 530.69531.7 706 546.69 547.7 707 560.72 561.7 708 573.76 574.8 709 560.72561.7 710 645.82 646.8 711 659.85 660.9 712 546.69 547.7 713 613.83614.8 714 546.60 647.7 715 573.76 574.8 716 545.71 546.7 717 545.71546.7 718 587.79 588.8 719 559.73 560.7 720 559.73 560.7 721 659.85660.9 722 488.61 489.6 723 471.58 472.6 725 465.62 466.6 726 383.51384.5 727 439.58 440.6 728 407.54 408.5 729 423.56 424.6 730 385.51386.5 731 415.56 416.6 732 385.53 386.4 733 433.53 434.5 734 419.5 420.5735 359.49 360.5

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, autoinjector devices orsuppositories; for oral parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the composition may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdividedinto unit dosage forms of the type described above containing from 5 toabout 1000 mg of the active ingredient of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders mediated by the ORL-1 receptordescribed in the present invention may also be carried out using apharmaceutical composition comprising any of the compounds as definedherein and a pharmaceutically acceptable carrier. The pharmaceuticalcomposition may contain between about 1 mg and 1000 mg, preferably about10 to 500 mg, of the compound, and may be constituted into any formsuitable for the mode of administration selected. Carriers includenecessary and inert pharmaceutical excipients, including, but notlimited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixers, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms may include suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methyl-cellulose and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

The compound of the present invention can also be administered viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders mediated by the ORL-1 receptor isrequired.

The daily dosage of the products may be varied over a wide range from 1to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.5, 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.01 mg/kg to about 30 mg/kg ofbody weight per day. Preferably, the range is from about 0.1 mg/kg toabout 10 mg/kg of body weight per day, and especially from about 0.5mg/kg to about 10 mg/kg of body weight per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

EXAMPLE 1 2-Thienylphenyl-2-ethanol

3-Bromophenethyl alcohol (4 ml, 29.8 mmol) was dissolved in1,2-dimethoxyethane (225 mL) and mixed with tetrakistriphenylphosphinepalladium[0] (2.6 g, 2.25 mmol) at room temperature. The reactionmixture was then added to a solution of 2-thienyl-boronic acid (12.6 g,99 mmol) and 1N NaHCO₃ (90 mL). The reaction mixture was heated toreflux under nitrogen atmosphere for 48 hours. The reaction mixture waspartitioned with water and ethyl acetate. The organic layer was driedwith MgSO₄, filtered through a plug of silica and the solvent wasevaporated in vacuo to yield a crude oil. The crude oil was purified viaflash chromatography (30% EtOAc/hexane) to yield the title compounds asan oil.

MS (chemical ionization)=221 (M+NH₄) ¹H NMR (300 MHz, CDCl₃) δ 1.3 (t,1H), 3.0 (t, 2H), 3.75 (q, 2H), 7.0-7.4 (m, 7H)

EXAMPLE 2 Methane Sulfonic Acid 2-(2-thien-2-yl-phenyl)-ethyl Ester

2-Thienylphenylethanol (13.6 mmol) and triethylamine (2.4 mL, 17.1 mmol)were dissolved in dichloromethane (50 mL). Methanesulfonylchloride (1.1mL, 14 mmol) was then added slowly. The reaction mixture was stirred atroom temperature for 1.5 hours. The reaction mixture was carefullypartitioned with water and dichloromethane. The organic layer was driedwith Na₂SO₄, filtered and the solvent evaporated in vacuo to yield thetitle compounds, which was used without further purification.

MS (chemical ionization)=300 (M+NH₄), 283 (MH+), 187, ¹H NMR (300 MHz,CDCl₃) δ 2.8 (s, 3H), 3.2 (t, 2H), 4.3 (t, 2H), 7.0 (m, 1H), 7.1 (m,1H), 7.2-7.5 (m, 5H)

EXAMPLE 31-Phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #581

Methane sulfonic acid 2-(2-thien-2-yl-phenyl)-ethyl ester (23.14 mmol)was combined in NMP (100 mL) with1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (5.08 g, 22 mmol) and DIPEA(5.11 mL, 27.8 mmol) in a reaction tube which was sealed and heated to70° C. overnight. The reaction mixture was partitioned with water andethyl acetate. The organic layer was dried with MgSO₄, filtered and thesolvent was evaporated in vacuo to yield a crude oil. The crude oil waspurified via flash chromatography (5% methanol/CH₂Cl₂) to yield thetitle compound as a solid.

MS (electrospray)=418.1 (MH+), 313.0 ¹H NMR (300 MHz, DMSO-d₆) δ 1.5 (d,2H), 2.4 (m, 4H), 2.6 (m, 4H), 2.85 (m, 2H), 4.55 (s, 2H), 6.7-6.8 (m,3H), 7.1-7.4 (m, 8H), 7.6 (s, 1H), 8.65 (s, 1H)

EXAMPLE 4(R)-3-Oxiranylmethyl-1-phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #520

1-Phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-one(0.7 g, 1.68 mmol) was dissolved in NMP (50 mL). To the mixture was thenadded sodium hydride (60% in mineral oil, 0.1, 2.52 mmol) and thereaction mixture stirred for 1 hour. S-(+)-epichlorohydrin (0.15 mL, 1.9mmol) was then added to the reaction mixture. The reaction mixture wasstirred overnight at room temperature. The reaction mixture waspartitioned with saturated sodium bicarbonate and ethyl acetate. Theorganic layer was then partitioned with water. The organic layer wasdried with MgSO₄, filtered and the solvent was evaporated in vacuo toyield a crude oil. The crude oil was purified via flash chromatography(80% EtOAc/hex) to yield the title compound as an oil.

MS (electrospray)=474.1 (MH+) ¹H NMR (300 MHz, CDCl₃) δ 1.6 (t, 2H),2.5-3.0 (m, 12H), 3.1-3.2 (m, 2H), 4.05 (d, 1H), 4.7 (d, 1H), 4.8 (d,1H), 6.8 (m, 2H), 7.0 (m, 1H), 7.2-7.4 (m, 9H).

EXAMPLE 53-[2-(S)-Hydroxy-3-(3-morpholin-4-yl-propylamino)-propyl]-1-phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #111

3-(R)-Oxiranylmethyl-1-phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triaza-spiro[4.5]decan-4-one(0.1 g, 0.21 mmol) was dissolved in absolute ethanol (2 mL), mixed with3-aminopropyl morpholino (90 μl, 0.63 mmol) and heated to 70° C.overnight. The solvent was evaporated and the resulting residue waspurified by reverse phase chromatography (AcCN/water) to yield the titlecompounds as a trifluoroacetate salt, as a solid.

MS (electrospray)=618.3 (MH+) ¹H NMR (300 MHz, CD₃OD) δ 2.0 (d, 2H), 2.2(m, 2H), 2.72-2.88 (m, 2H), 3.0-4.3 (m, 23H), 4.8-5.05 (m, 6H), 6.8-7.5(m, 12H).

EXAMPLE 6(S)-3-Oxiranylmethyl-1-phenyl-8-[2-(2-thienyl-phenyl)-ethyl]-1,3,8-triazaspiro[4.5]decan-4-oneCompound #519

1-Phenyl-8-[2-(2-thienyl-phenyl)-ethyl]-1,3,8-triazaspiro[4.5]decan-4-one(0.13 g, 0.3 mmol) was dissolved in NMP (10 mL). To the mixture was thenadded sodium hydride (60% in mineral oil, 31 mg, 0.8 mmol) and thereaction mixture stirred for 1 hour. R-(−)-epichlorohydrin 927 μL, 0.35mmol) was then added to the reaction mixture, which was then stirredovernight at room temperature. The reaction mixture was partitioned withsaturated sodium bicarbonate and ethyl acetate. The organic layer wasthen partitioned with water. The organic layer was dried with MgSO₄,filtered and the solvent evaporated in vacuo to yield a crude oil. Thecrude oil was purified via flash chromatography (80% EtOAc/hexanes) toyield the title compound as an oil.

MS (electrospray)=474.1 (MH+) ¹H NMR (300 MHz, CDCl₃) δ 1.65 (t, 2H),2.0 (q, 1H), 2.4 (t, 1H), 2.5-3.0 (m, 11H), 3.2 (m, 1H), 3.3 (t, 1H),4.0 (d, 1H), 4.7 (d, 1H), 4.8 (d, 1H), 6.9 (m, 2H), 7.0 (m, 1h),7.15-7.4 (m, 9H).

EXAMPLE 73-[2-(R)-hydroxy-3-(3-morpholin-4-yl-propylamino)-propyl]-1-phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-13,8-triazaspiro[4.5]decan-4-one Compound #112

3-(S)-Oxiranylmethyl-1-phenyl-8-[2-(2-thien-2-yl-phenyl)-ethyl]-1,3,8-triazaspiro[4.5]decan-4-one(0.13 g, 0.27 mmol) was dissolved in absolute ethanol (2 mL), mixed with3-aminopropylmorpholino (100 μL, 0.68 mmol) and heated with stirring at70° C. overnight. The solvent was evaporated and the resulting residuewas purified by reverse phase chromatography (Acetonitrile/water) toyield the title compound as a trifluoroacetate salt as a solid.

MS (electrospray)=618.3 (MH+) ¹H NMR (300 MHz, CD₃OD) δ 2.0 (d, 2H), 2.2(m, 2H), 2.75-2.9 (m, 2H), 3.0-4.3 (m, 23H), 4.8-5.05 (m, 6H), 6.8-7.5(m, 12H).

EXAMPLE 8 1-bromo-acenaphthene

Acenaphthen-1-ol (88 mol) was dissolved in diethyl ether (150 mL) andcooled down to 0° C. Phosphorous tribromide (3.2 mL, 35 mmol) was thenadded slowly under nitrogen atmosphere. The reaction mixture was stirredfor 30 minutes at room temperature and cooled to 0° C. The reactionmixture was partitioned with water and diethyl ether. The organic layerwas dried over Na₂SO₄, filtered and the solvent evaporated in vacuo toyield the title compound as a yellow solid.

EXAMPLE 98-Acenaphthen-1-yl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-oneCompound # 500

1-Bromo-acenaphthene (20.5 g, 87.9 mmol) and1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (9.15 g, 36.6 mmol)were dissolved in N,N-dimethylformamide (190 mL). Potassium carbonate(15.15 g, 110 mmol) was then added and the reaction mixture was stirredat room temperature under a nitrogen atmosphere for 18 hours. Thereaction mixture was partitioned with water and diethyl ether. The titlecompound precipitated from the organic layer as an off-white solid.

¹H NMR (300 MHz, CDCl₃) δ7.68-7.66 (91H, m), 7.60 (1H, d, J=8.2 Hz),7.53-7.49 (2H, m), 7.43 (1H, t, J=8.1 Hz), 7.26 (1H, d, J=7.8 Hz),7.04-6.94 (4H, m), 6.67 (1H, br, s), 4.95 (1H, br, s), 4.66-4.63 (2H,m), 3.51 (1H, d), 3.34 (1H, dd J=7.6 and 17.5 Hz), 3.13-2.94 (2H, m),2.83 (1H, br, s), 2.43 (1H, br, a), 2.24 (1H, m), 1.80-1.66 (3H, m) MS(ES⁺) m/z 402.1 (M+H)⁺

Chiral resolution: The racemate prepared as described above was resolvedusing a CHIRALCEL OD-H column with methanol as mobile phase andgenerated the two pure enantiomers R (RT=6.174 minutes, ee>99%) and S(RT=10.175 minutes, ee>99%).

EXAMPLE 101-(4-fluorophenyl)-8-(2-hydroxy-cycloheptyl)-1,3,8-triazaspiro[4.5]decan-4-oneCompound #549

1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (0.15 g, 0.6 mmol)was dissolved in dichloromethane (1 mL) and 1,2-dichloromethane (0.25mL) under a nitrogen atmosphere. The reaction mixture was then addedslowly at 0° C. to 1.9M triethyl aluminum in toluene (0.315 mL, 0.6mmol). After stirring for 30 minutes at room temperature, to thereaction mixture was added slowly a solution of8-oxa-bicyclo[5.1.0]octane (68 mg, 0.6 mmol) in dichloromethane (16 mL).The reaction mixture was stirred at room temperature under a nitrogenatmosphere for 13 days and then partitioned with 1N NaOH and DCM. Theorganic layer was dried over Na₂SO₄, filtered and the solvent evaporatedin vacuo to yield a crude oil. The crude oil was purified via flashchromatography (2% methanol/DCM) to yield the title compound as an oil.

¹H NMR (300 MHz, CDCl₃) δ7.05-6.88 (4H, m), 4.69 (s, 2H), 3.44-3.31 (2H,m), 2.96-2.88 (1H, m), 2.73-2.69 (1H, m), 2.56-2.53 (1H, m), 2.42-2.17(3H, m), 2.11-2.02 (1H, m), 1.94-1.87 (1H, m), 1.78 (1H, d), 1.72-1.19(11H, m) MS (ES⁺) m/z 362.3 (M+H)⁺.

EXAMPLE 11(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triazaspiro[4.5]decan-4-oneCompound #556

(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one(1.5 g, 3.736 mmol) was dissolved in N,N-dimethylformamide (10.0 mL). Tothe reaction mixture was then added at 0° C. sodium hydride (60% inmineral oil, 0.195 g, 4.856 mmol) under nitrogen atmosphere. Thereaction mixture was stirred at 0° C. for 40 minutes and then warmed toroom temperature. To the reaction mixture was then added(S)-epichlorhydrin (0.87 mL, 11.208 mmol). The reaction mixture wasstirred at room temperature under nitrogen atmosphere for 18 hours andpartitioned with water and ethyl acetate. The organic layer was driedwith Na₂SO₄, filtered and the solvent evaporated in vacuo to yield acrude oil. The crude oil was purified via flash chromatography (1.5%methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ7.70-7.65 (1H, m), 7.60 (1H, d, J=8.2 Hz),7.54-7.49 (2H, m), 7.44 (1H, t), 7.26 (1H, d), 7.05-6.93 (4H, m), 4.95(1H, dd, J=3.4 and 7.8 Hz), 4.77-4.74 (1H, m), 4.66-4.64 (1H, m), 4.0(1H, d, J=12.5 Hz), 3.56-3.32 (2H, m), 3.21-3.03 (4H, m), 2.83-2.80 (2H,m), 2.59-2.55 (1H, m), 2.46-2.30 (2H, m), 2.27-2.21 (1H, m), 1.77-1.60(2H, m) MS (ES⁺) m/z 458.3 (M+H)⁺.

EXAMPLE 12(R)-8-Acenaphthen-1-yl-3-(3-{[2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-amino}-(R)-2-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #339

8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(1.5 g, 3.28 mmol), [2-(3,4-dimethoxy-phenyl)-ethyl]-methyl-aminehydrochloride (2.3 g, 9.92 mmol) and N,N-diisopropylethylamine (5 mL,28.7 mmol) were dissolved in ethanol (40 mL). The reaction mixture washeated at 80° C. for 18 hours, then cooled to room temperature and thesolvent evaporated in vacuo to yield an oil. The oil was partitionedwith water and ethyl acetate. The organic layer was dried with Na₂SO₄,filtered and the solvent evaporated in vacuo to yield a crude oil. Thecrude oil was purified via flash chromatography (2% [methanol in ammonia2.0M]/dichloromethane) to yield the title compound as a foam.

Chiral resolution: Diastereoisomers were separated using a CHIRALCELOD-H column with methanol as mobile phase and generated the two purediastereoisomers R, R and R, S.

¹H NMR (300 MHz, CDCl₃) δ7.69-7.65 (1H, m), 7.60 (1H, d, J=8.2 Hz),7.54-7.50 (2H, m), 7.44 (1H, t), 7.27-7.25 (1H, m), 7.04-6.92 (4H, m),6.77-6.64 (3H, m), 4.97-4.94 (1H, m), 4.79-4.71 (2H, m), 3.82 (3H, s),3.81 (3H, s), 3.58-3.51 (3H, m), 3.38-3.02 (5H, m), 2.84-2.80 (1H, m),2.77-2.53 (4H, m), 2.49-2.26 (7H, m), 1.76-1.59 (2H, m) MS (ES⁺) m/z653.4 (M+H)⁺.

EXAMPLE 131-(4-Fluoro-phenyl)-8-naphthalen-1-ylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #507

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (1.0 g, 4.01mmol) and naphthalene-1-carbaldehyde (0.75 g, 4.81 mmol) were dissolvedin dry tetrahydrofuran (60 mL). To the reaction mixture was then addedat 0° C. sodium triacetoxyborohydride (1.27 g, 6.01 mmol) under nitrogenatmosphere and the reaction mixture was stirred at room temperature for18 hours. The reaction mixture was then partitioned with 1N NaOH andethyl acetate. The organic layer was washed with brine, dried withNa₂SO₄, filtered and the solvent evaporated in vacuo to yield a crudeoil. The crude oil was purified via flash chromatography (3%methanol/dichloromethane) to yield the title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ8.39-8.36 (1H, m), 7.87-7.75 (2H, m), 7.56-7.37(4H, m), 6.99-6.85 (4H, m), 4.67 (2H, s), 3.97 (2H, s), 2.91-2.83 (4H,m), 2.42-2.31 (2H, m), 1.75-1.71 (2H, m) MS (ES⁺) m/z 390.1 (M+H)⁺.

EXAMPLE 141-(4-Fluoro-phenyl)-8-naphthalen-1-ylmethyl-(R)-3-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #514

(R)-1-(4-Fluoro-phenyl)-8-naphthalen-1-ylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.218 g, 0.559 mmol) was dissolved in N,N-dimethylformamide (2.2 mL).To the reaction mixture was then added at 0° C. sodium hydride (60% inmineral oil, 30 mg, 0.727 mmol) under nitrogen atmosphere and thereaction mixture was stirred at 0° C. for 40 minutes. To the reactionmixture was then added (S)-epichlorhydrin (0.13 mL, 1.679 mmol) at 0° C.The reaction mixture was stirred at room temperature under nitrogenatmosphere for 18 hours and partitioned with water and ethyl acetate.The organic layer was washed with brine, dried with Na₂SO₄, filtered andthe solvent evaporated in vacuo to yield a crude oil. The crude oil waspurified via flash chromatography (2% methanol/dichloromethane) to yieldthe title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ8.38-8.35 (1H, m), 7.87-7.75 (2H, m), 7.56-7.37(4H, m), 6.99-6.86 (4H, m), 4.78-4.65 (2H, m), 4.08-3.97 (3H, m),3.21-3.12 (2H, m), 2.95-2.82 (5H, m), 2.61-2.59 (1H, m), 2.40-2.30 (2H,m), 1.72-1.59 (2H, m) MS (ES⁺) m/z 446.3 (M+H)⁺.

EXAMPLE 151-(4-Fluoro-phenyl)-8-(5-phenyl-thien-2-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #546

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.15 g, 0.601mmol) and 5-phenyl-thienyl-2-carbaldehyde (0.136 g, 0.722 mmol) weredissolved in dry tetrahydrofuran (12 mL). To the reaction mixture wasthen added at 0° C. sodium triacetoxyborohydride (0.192 g, 0.902 mmol)under nitrogen atmosphere and the reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was partitioned with 1NNaOH and ethyl acetate. The organic layer was washed with brine, driedwith Na₂SO₄, filtered and the solvent evaporated in vacuo to yield acrude oil. The crude oil was purified via flash chromatography (2%methanol/dichloromethane) to yield the title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ7.59-7.56 (2H, m), 7.38-7.33 (2H, m), 7.27-7.22(1H, m), 7.18-7.13 (1H, m), 7.05-6.92 (4H, m), 6.87 (1H, d, J=3.6 Hz),6.26 (1H, br s), 4.67 (2H, s), 3.75 (2H, s), 2.87-2.78 (4H, m),2.40-2.30 (2H, m), 1.76 (2H, d, J=14.1 Hz) MS (ES⁺) m/z 422.1 (M+H)⁺.

EXAMPLE 16(R)-1-(4-Fluoro-phenyl)-3-oxiranylmethyl-8-(5-phenyl-thien-2-yl-methyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #541

1-(4-Fluoro-phenyl)-8-(5-phenyl-thien-2-yl-methyl)-1,3,8-triaza-spiro[4.5]decan-4-one(0.105 g, 0.249 mmol) was dissolved in N,N-dimethylformamide (2.5 mL).To the reaction mixture was then added at 0° C. sodium hydride (60% inmineral oil, 13 mg, 0.323 mmol) under nitrogen atmosphere and thereaction mixture was stirred at 0° C. for 40 minutes. To the reactionmixture was then added (S)-epichlorhydrin (0.058 mL, 0.747 mmol) at 0°C. The reaction mixture was stirred at room temperature under nitrogenatmosphere for 18 hours and partitioned with water and ethyl acetate.The organic layer was washed with brine, dried with Na₂SO₄, filtered andthe solvent evaporated in vacuo to yield a crude oil. The crude oil waspurified via flash chromatography (2% methanol/dichloromethane) to yieldthe title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ7.59-7.55 (2H, m), 7.38-7.33 (2H, m), 7.27-7.22(1H, m), 7.14 (1H, d, J=3.6 Hz), 7.05-6.92 (4H, m), 6.87 (1H, d, J=3.5Hz), 4.77 (1H, d, J=4.8 Hz), 4.66 (1H, d, J=4.8 Hz), 4.06-3.99 (1H, m),3.76 (2H, s), 3.20-3.13 (2H, m), 2.95-2.82 (3H, m), 2.60-2.58 (1H, m),2.38-2.30 (2H, m), 1.75-1.67 (2H, m) MS (ES⁺) m/z 478.2 (M+H)⁺.

EXAMPLE 171-(4-Fluoro-phenyl)-8-(4-propyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #504

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.25 g, 1.00mmol) was dissolved in dry toluene (10 mL). To the reaction mixture wasthen added 4-propyl-cyclohexanone (0.14 g, 1.00 mmol), powder molecularsieve 4A (0.5 g) and the reaction mixture was refluxing for 18 hoursunder nitrogen atmosphere. The reaction mixture was cooled to roomtemperature and filtered through Celite. The Celite cake was washed withdry dichloromethane and the combined filtrate evaporated in vacuo todryness. The residue was dissolved in dry tetrahydrofuran (4 mL) and drymethanol (0.5 mL). To the solution was then added sodiumcyanoborohydride (21 mg), the pH of the solution was adjusted to pH 4with a few drops of glacial acetic acid and the reaction mixture wasstirred for 48 hours at room temperature under nitrogen atmosphere. Thereaction mixture was partitioned with 1N NaOH and ethyl acetate. Theorganic layer was dried with Na₂SO₄, filtered and the solvent evaporatedin vacuo to yield a crude oil. The crude oil was purified via flashchromatography (gradient 2-4% methanol/dichloromethane) to yield thetitle compound.

¹H NMR (300 MHz, CDCl₃) δ7.02-6.93 (4H, m), 6.54 (1H, br d, J=9.1 Hz),4.67 (2H, s), 3.05-2.70 (4H, m), 2.38-2.15 (3H, m), 1.9-1.11 (15H, m),0.94-0.84 (3H, m) MS (ES⁺) m/z 374.0 (M+H)⁺.

EXAMPLE 18 1-Bromomethyl-8-methyl-naphthalene

1,8-Dimethyl-naphthalene (1.30 g, 8.32 mmol) was dissolved in dry carbontetrachloride (80 mL). To the reaction mixture was addedN-bromosuccinimide (1.39 g, 7.82 mmol), dibenzoyl peroxide (6 mg,catalyst) and the reaction mixture was refluxing for 6 hours undernitrogen atmosphere. The reaction mixture was cooled to roomtemperature, a precipitate formed on cooling and the precipitate wasseparated by filtration. The filtrate was evaporated in vacuo to yieldthe title compound as a solid which was used in further steps withoutadditional purification.

EXAMPLE 191-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-oneCompound #547

1-Bromomethyl-8-methyl-naphthalene (1.72 g, 7.31 mmol) and1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (1.29 g, 5.17mmol) were dissolved in N,N-dimethylformamide (50 mL). Potassiumcarbonate (2.4 g, 15.52 mmol) and potassium iodide (0.02 g) were addedand the reaction mixture was stirred at 30° C. under nitrogen atmospherefor 18 hours. The reaction mixture was partitioned with water and ethylacetate. The organic layer was washed with brine, dried with Na₂SO₄,filtered and the solvent evaporated in vacuo to yield a crude solid. Thecrude solid was recrystallized from diethyl ether to yield the titlecompound as a solid.

¹H NMR (300 MHz, CDCl₃) δ7.79-7.76 (1H, m), 7.72-7.69 (1H, m), 7.39-7.30(4H, m), 6.98-6.92 (2H, m), 6.87-6.82 (2H, m), 6.24 (1H, br s), 4.66(2H, s), 4.01 (2H, s), 3.12 (3H, s), 2.86-2.78 (4H, m), 2.33-2.23 (2H,m), 1.72 (2H, d, J=14.1 Hz) MS (ES⁺) m/z 404.2 (M+H)⁺.

EXAMPLE 201-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #553

1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one(0.91 g, 2.25 mmol) was dissolved in N,N-dimethylformamide (10.5 mL). Tothe reaction mixture was then added at 0° C. sodium hydride (60% inmineral oil, 117 mg, 2.93 mmol) under nitrogen atmosphere and thereaction mixture was stirred at 0° C. for one hour, then warmed to roomtemperature. To the reaction mixture was then added (S)-epichlorhydrin(0.53 mL, 6.76 mmol). The reaction mixture was stirred at roomtemperature under nitrogen atmosphere for 18 hours and partitioned withwater and ethyl acetate. The organic layer was washed with brine, driedwith Na₂SO₄, filtered and the solvent evaporated in vacuo to yield acrude oil. The crude oil was purified via flash chromatography (2.5%methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ7.78-7.75 (1H, m), 7.71-7.68 (1H, m), 7.39-7.30(4H, m), 6.99-6.92 (2H, m), 6.88-6.83 (2H, m), 4.76 (1H, d, J=4.8 Hz),4.64 (1H, d, J=4.8 Hz), 4.0 (2H, s), 3.21-3.11 (6H, m), 2.86-2.78 (5H,m), 2.60-2.58 (1H, m), 2.30-2.22 (2H, m), 1.70-1.62 (2H, m) MS (ES⁺) m/z460.2 (M+H)⁺.

EXAMPLE 213-{3-[8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl}-2-(R)-hydroxy-propylsulfanyl]-2-acetylamino-(R)-propionicAcid Compound #100

8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.022 g, 0.048 mmol) and N-acetyl-L-cysteine (0.03 g, 0.184 mmol) weredissolved in ethanol (1 mL). The reaction mixture was heated at 80° C.for 18 hours, then cooled to room temperature and the solvent evaporatedin vacuo to yield an oil. The oil was partitioned with water and ethylacetate. The organic layer was dried with Na₂SO₄, filtered and thesolvent evaporated in vacuo to yield a crude oil. The crude oil waspurified via preparative TLC plate (10% methanol/dichloromethane) toyield the title compound as an oil.

EXAMPLE 228-Cyclooctylmethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompounds #582

Cyclooctanecarbaldehyde (0.676 g, 4.8 mmol) synthesized according to theprocedure described in Kawamoto, H. et al. Tetrahedron 2001, 57, 981-986was reacted with 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one(1 g, 4 mmol) in tetrahydrofuran (anhydrous, 100 mL), with the additionof sodium triacetoxyborohydride (1.2 g, 6 mmol) at 0° C. The reactionwas then stirred overnight at room temperature. The organic layer waspartitioned with 1N sodium hydroxide, water and brine. The organic layerwas dried with sodium sulfate and filtered to yield a clear residue.Purification of the residue by flash chromatography yielded the titlecompound as a white powder.

MS (electrospray)=374.1 (MH+) ¹H NMR (300 MHz, CDCl₃) δ1.1-1.9 (m, 15H),2.1 (d, 2H), 2.2-2.4 (m, 2H), 2.7 (d, 4H), 3.3 (d, 2H), 4.7 (s, 2H), 6.4(s, 1H), 6.8-7.0 (m, 4H).

EXAMPLE 238-Cyclooctylmethyl-1-(4-fluoro-phenyl)-(R)-3-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #540

8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one(4, 3 g, 8 mmol) was dissolved with NMP (150 mL) and stirred at 0° C.Sodium hydride (60% dispersion in oil, 0.75 g, 18.7 mmol) was added tothe reaction mixture which was then stirred an additional 30 minutes at0° C. S-(+)-epichlorohydrin (1.88 ml, 24 mmol) was added and thereaction was stirred overnight at room temperature. The reaction wasthen partitioned with water and ethyl acetate. The organic was driedwith sodium sulfate and filtered. The solvent was evaporated to yieldthe title compound as an oil.

MS (electrospray)=430.5 (MH+) ¹H NMR (300 MHz, CDCl₃) δ1.1-1.9 (m, 17H),2.15 (d, 2H), 2.2-2.4 (m, 2H), 2.5-2.85 (m, 4H), 3.1 (m, 2H), 4.0 (m,1H), 4.65 (d, 1H), 4.75 (d, 1H), 6.8-7.0(m, 4H)

EXAMPLE 243-[3-(Benzyl-butyl-amino)-2-(S)-hydroxy-propyl]-8-cyclooctylmethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #64

Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(3.4 g, 8 mmol) was dissolved in absolute ethanol (75 mL), mixed withN-butylbenzylamine (3.1 mL, 17.6 mmol) and heated at reflux overnight.The solvent was evaporated and the resulting residue was purified bycolumn chromatography (5% MeOH/CH₂Cl₂) to yield the free base as an oil.The oil (2.2 g, 3.7 mmol) was dissolved in diethyl ether (10 mL) andreacted with HCl (11 mL, [1M in diethylether]) at 0° C. He resultingcrystals were collected by filtration and recrystallized with ethanol toyield 1 g the title compound white powder.

MS (electrospray)=593.5 (MH+), 592.6 ¹H NMR (300 MHz, CD₃OD) δ1.1 (m,3H), 1.3-1.9 (m, 15H), 2.1 (m, 2H), 2.4 (m, 2H), 2.9-3.6 (m, 14H),3.65-3.8 (m, 2H), 4.2 (m, 1H), 4.3-4.3 (m, 3H), 4.8 (m, 2H), 7.0-7.2 (m,4H), 7.4-7.7 (m, 5H)

EXAMPLE 258-Cyclooctylmethyl-3-{3-[2-(3,4-dimethoxy-phenyl)-ethoxy]-2-(R)-hydroxy-propyl}-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #105

3,4-Dimethoxyphenethylalcohol was dissolved in NMP (2 mL) and stirredfor 30 min. NaH (60% dispersion in oil) was added and the mixture wasstirred for thirty minutes.8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.2 g, 0.46 mmol) was added and the reaction was stirred overnight atroom temperature. The reaction was partitioned with saturated NaHCO₃solution and ethyl acetate. The organic layer was dried with MgSO₄,filtered and the solvent evaporated in vacuo to yield crude product.Purification by reverse phase chromatography (AcCN/water) yielded thetitle compound as a trifluoroacetate salt as a solid.

MS (electrospray)=612.1 (MH+), 522.0, 402.2 ¹H NMR (300 MHz, CD₃OD)δ1.3-1.8 (m, 14H), 2.0-2.1 (m, 4H), 2.2-2.4 (m, 2H), 2.8 (t, 2H), 3.0(d, 2H), 3.35-3.8 (m, 13H), 3.9 (m, 4H), 4.7 (m, 2H), 6.8 (m, 3H), 7.1(m, 4H)

EXAMPLE 262-Acetylamino-3-{3-[8-cyclooctylmethyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl]-2-(R)-hydroxy-propylsulfanyl}-propionicAcid Compound #100

1-(4fluorophenyl)-3R-oxarinyl-methyl-8-cyclooctylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.06 g, 0.14 mmol) was dissolved in absolute ethanol (1 mL), mixed withN-acetylcysteine (68 mg, 0.42 mmol) and heated to 70° C. overnight. Thesolvent was evaporated and the resulting residue was purified by reversephase chromatography (AcCN/water) to yield the title compounds as atrifluoroacetate salt as a solid.

MS (electrospray)=593.8 (MH+).

EXAMPLE 271-(4-Fluoro-phenyl)-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #583

Pentamethylbenzaldehyde (4 g, 23 mmol, commercially available) wasreacted with 1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (5.5g, 20 mmol) in tetrahydrofuran (anhydrous, 250 mL), with addition ofsodium triacetoxyborohydride (8.2 g, 42 mmol) at 0° C. The reaction wasthen stirred overnight at room temperature. The organic layer waspartitioned with 1N sodium hydroxide, water and brine. The organic layerwas dried with sodium sulfate and filtered to yield the title compoundas a white powder.

MS (electrospray)=410.5 (MH+), 250.0 ¹H NMR (300 MHz, DMSO-d₆) δ1.6 (d,2H), 2.2-2.3 (m, 17 H), 2.6-2.8 (m, 4H), 3.55 (s, 2H), 4.5 (s, 2H), 6.8(m, 2H), 7.1 (t, 2H), 8.65 (s, 1H).

EXAMPLE 281-(4-Fluoro-phenyl)-3R-oxiranylmethyl-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #584

1-(4-Fluoro-phenyl)-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.6 g, 1.46 mmol) was dissolved with NMP (5 mL) and stirred at roomtemperature. Sodium hydride (60% dispersion in oil, 0.11 g, 1.6 mmol)was added and the mixture stirred an additional 30 minutes.S-(+)-epichlorohydrin (0.3 ml, 3.2 mmol) was added and the reaction wasstirred overnight at room temperature. The reaction was then partitionedwith water and ethyl acetate. The organic was dried with sodium sulfateand filtered. The solvent was evaporated to yield the title compounds asan oil.

MS (electrospray)=466.1 (MH+)

EXAMPLE 293-[3-(Benzyl-butyl-amino)-2-(S)-hydroxy-propyl]-1-(4-fluoro-phenyl)-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #280

1-(4-Fluoro-phenyl)-3R-oxiranylmethyl-8-pentamethylphenylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.1 g, 0.21 mmol) was dissolved in absolute ethanol (75 mL), mixed withN-butylbenzylamine (0.1 mL, 0.6 mmol) and heated at reflux overnight.The solvent was evaporated and the resulting residue was purified byreverse phase chromatography (AcCN/water) to yield the title compound asan oil.

MS (electrospray)=629.2 (MH+), 468.9, 315.3, 311.9, 161.1 ¹H NMR (300MHz, CD₃OD) δ1.0 (m, 3H), 1.3 (m, 2 H), 1.8 (m, 2H), 1.9 (m, 2H), 2.25(d, 9H), 2.3(s, 6H), 3.2 (m, 3H), 3.4 (m, 4H), 3.9 (m, 3H), 4.15 (m,1H), 4.4 (m, 4H), 4.8 (m, 2H), 7.0 (m, 3H), 7.5 (m, 9H).

EXAMPLE 308-(2-Chloro-6-trifluoromethyl-benzyl)-1-(4-fluoro-phenyl)-3R-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #578

8-(2-Chloro-6-trifluoromethyl-benzyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one(0.3 g, 0.68 mmol) was dissolved with NMP (20 mL) and stirred at roomtemperature. Sodium hydride (60% dispersion in oil, 0.066 g, 0.95 mmol)was added and the mixture was stirred an additional 30 minutes.S-(+)-epichlorohydrin (0.14 ml, 1.5 mmol) was added and the reaction wasstirred overnight at room temperature. The reaction was then partitionedwith water and ethyl acetate. The organic was dried with sodium sulfateand filtered. The solvent was evaporated to yield the title compound asan oil.

¹H NMR (300 MHz, CDCl₃) δ1.6 (m, 2H), 2.3 (m, 2H), 2.7 (m, 2H), 2.9 (bt,2H), 3.1 (m, 1H), 3.8 (s, 2H), 4.0 (d, 1H), 4.6 (d, 1H), 4.8 (d, 2H),6.8 (m, 2H), 6.95 (m, 2H), 7.2 (t, 1H), 7.6 (t, 2H).

EXAMPLE 313-[3-(Benzyl-butyl-amino)-2-(S)-hydroxy-propyl]-8-(2-chloro-6-trifluoromethyl-benzyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #456)

8-(2-Chloro-6-trifluoromethyl-benzyl)-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.05 g, 0.1 mmol) was dissolved in absolute ethanol (0.5 mL), mixedwith N-butylbenzylamine (0.05 mL, 0.4 mmol) and heated at refluxovernight. The solvent was evaporated and the resulting residue waspurified by reverse column chromatography (AcCN/water) to yield thetitle compound as an oil.

MS (electrospray)=661.0 (MH+), 571.1, 331.4

EXAMPLE 32{1-[{3-[8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl]-2-(S)-hydroxy-propyl}-(4-methyl-benzyl)-carbamoyl]-2-methyl-propyl}-carbamicAcid tert-butyl Ester Compound #79

8-Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-[2-hydroxy-3-(4-methyl-benzylamino)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-one(0.05 g, 0.091 mmol) was dissolved in DMF (1 mL), mixed with BocD-Valine(0.02 g, 0.091 mmol), HBTU (0.035 g, 0.09 mmol) anddiisopropylethylamine (0.1 mL) and stirred overnight at roomtemperature. The reaction mixture was partitioned with saturated NaHCO₃and ethyl acetate. The organic layer dried with MgSO₄, filtered and thesolvent evaporated in vacuo to yield the title compound as an oil.

MS (electrospray)=751.5 (MH+), 749.8, 373.6, 372.8, 203.1, 171.1

EXAMPLE 338-Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-[2-(S)-hydroxy-3-(pyridin-4-ylamino)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #36

Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.5 g, 1.16 mmol) was dissolved in absolute ethanol (1 mL), mixed with4-Aminopyridine (0.5 mL, 5.3 mmol) and heated at reflux overnight. Thesolvent was evaporated and the resulting residue was purified by reversephase column chromatography (Acetonitrile/water) to yield the titlecompound as an oil.

¹H NMR (300 MHz, CD₃OD) δ1.35 (m, 2H), 1.5-1.7 (m, 13 H), 1.9 (s, 9H),1.95 (m, 1H), 2.4 (m, 2H), 3.1 (d, 2H), 3.2 (m, 2H), 3.4 (m, 2H), 3.55(d, 2H), 4.0 (m, 1H), 4.15 (m, 1H), 4.3 (m, 1H), 6.8 (d, 2H), 7.1(m,4H), 8.1(d, 2H).

EXAMPLE 343-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #438

1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.06 g, 0.13 mmol) was dissolved in ethyl alcohol (2 mL) and methylalcohol (0.4 mL). To the solution was then added concentrated ammoniumhydroxide (1 mL) and the reaction mixture was stirred at 40° C. for twohours in a pressure flask. The solvent was then evaporated in vacuo toyield a crude oil. The crude oil was purified via flash chromatography(5.0% ammonia 2.0 M in methanol/dichloromethane) to yield the titlecompound as a foam.

¹H NMR (400 MHz, CDCl₃) δ7.77-7.75 (1H, m), 7.71-7.68 (1H, m), 7.37-7.30(4H, m), 6.97-6.91 (2H, m), 6.87-6.83 (2H, m), 4.74 (2H, s), 4.0 (2H,s), 3.79-3.74 (1H, m), 3.57-3.52 (1H, m), 3.41-3.36 (1H, m), 3.11 (3H,s), 2.91-2.74 (4H, m), 2.66-2.61 (1H, m), 2.30-2.23 (2H, m), 1.66 (2H,d, J=13.7 Hz) MS (ES⁺) m/z 477.1 (M+H)⁺.

EXAMPLE 35(R)-8-Acenaphthen-1-yl-3-(3-amino-2-hydroxy-(S)-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #424

(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.514 g, 1.123 mmol) was dissolved in ethyl alcohol (16 mL). To thesolution was then added concentrated ammonium hydroxide (8 mL) and thereaction mixture was stirred at 40° C. for two hours and a half in apressure flask. The solvent was then evaporated in vacuo to yield thetitle compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ7.68-7.65 (1H, m), 7.60 (1H, d, J=8.2 Hz),7.52-7.49 (2H, m), 7.43 (1H, t), 7.26 (1H, d), 7.03-6.94 (4H, m),4.97-4.94 (1H, m), 4.76-4.72 (2H, m), 3.74 (1H, br s), 3.55-3.48 (2H,m), 3.38-3.32 (2H, m), 3.16-3.03 (2H, m), 2.88-2.82 (2H, m), 2.59 (1H,br s), 2.44-2.41 (2H, m), 2.31-2.24 (1H, m), 1.76-1.62 (2H, m) MS (ES⁺)m/z 475.2 (M+H)⁺.

EXAMPLE 36(R)8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(2-hydroxy-3-methylamino-(S)-propyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #437

(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.045 g, 0.098 mmol) was dissolved in ethyl alcohol (2 mL). To thesolution was then added a solution of 2.0M methylamine in THF (1 mL) andthe reaction mixture was stirred at 40° C. for two hours and a half in apressure flask. The solvent was then evaporated in vacuo to yield thetitle compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ7.68-7.64 (1H, m), 7.59 (1H, d, J=8.2 Hz),7.53-7.49 (2H, m), 7.45 (1H, t), 7.26-7.24 (1H, m), 7.03-6.94 (4H, m),4.96-4.93 (1H, m), 4.78-4.73 (2H, m), 3.86-3.83 (1H, m), 3.55-3.47 (2H,m), 3.37-3.30 (2H, m), 3.16-2.99 (2H, m), 2.87-2.79 (2H, m), 2.70-2.66(1H, m), 2.52-2.23 (6H, m), 1.75-1.61 (2H, m) MS (ES⁺) m/z 489.3 (M+H)⁺.

EXAMPLE 378-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-hydroxy-3-(pyridin-4-ylamino)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #327

8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.100 g, 0.21 mmol) was dissolved in absolute ethyl alcohol (0.5 mL),mixed with 4-aminopyridine (0.2 mL) and heated at reflux overnight. Thesolvent was evaporated and the resulting residue was purified by reversephase chromatography (MeCN/water) to yield the title compound as an oil.

EXAMPLE 38(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-hydroxy-3-(pyridin-2-ylamino)-(R)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #421

Sodium amide (0.0085 g, 0.21 mmol) and 2-aminopyridine (0.0165 g, 0.17mmol) were suspended in toluene (0.25 mL) and benzene (0.15 mL). To thereaction mixture was then added(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.100 g, 0.21 mmol). The mixture was refluxed overnight under nitrogen,cooled down to room temperature and partitioned with brine anddichloromethane. The organic layer was washed with brine, dried withNa₂SO₄, filtered and the solvent evaporated in vacuo to yield a crudeoil. The crude oil was purified via flash chromatography (3.25% ammonia2.0 M in methanol/dichloromethane) to yield the title compound as anoil.

¹H NMR (300 MHz, CDCl₃) δ7.98-7.96 (1H, m), 7.69-7.65 (1H, m), 7.60 (1H,d, J=8.2 Hz), 7.53-7.51 (2H, m), 7.47-7.40 (1H, m), 7.28-7.26 (1H, m),7.03-6.92 (4H, m), 6.66-6.47 (3H, m), 5.08-5.04 (1H, m), 4.98-4.94 (1H,m), 4.79-4.73 (2H, m), 4.0-3.94 (1H, m), 3.72-3.61 (2H, m), 3.57-3.49(1H, m), 3.40-3.28 (2H, m), 3.14-3.02 (2H, m), 2.85-2.81 (1H, m),2.44-2.26 (3H, m), 1.74-1.25 (2H, m) MS (ES⁺) m/z 552.3 (M+H)⁺.

EXAMPLE 391-(4-Fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylicAcid tert-butyl Ester Compound #535

Di-tert-butyl dicarbonate (2.2 g, 10.0 mmol) and1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (2.5 g, 10.0mmol) were dissolved in dioxane (50 mL) and water (100 mL). Sodiumhydrogeno carbonate (1.7 g, 20 mmol) was then added and the reactionmixture was stirred at room temperature under nitrogen atmosphere for 18hours. The reaction mixture was concentrated in vacuo and partitionedwith water and ethyl acetate. The organic layer was washed with brine,dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yielda solid. Recrystallization from hot ethyl acetate yielded the titlecompound as a white solid.

¹H NMR (300 MHz, CDCl₃) δ8.25 (1H, br s), 7.0-6.95 (2H, m), 6.82-6.77(2H, m), 4.71 (2H, s), 4.08-3.8 (2H, m), 3.65-3.40 (2H, m), 2.35-2.15(2H, m), 1.8-1.65 (2H, m), 1.48 (9H, s) MS (ES⁺) m/z 372.1 (MNa)⁺.

EXAMPLE 408-Ethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one Compound#536

2-iodoethane (0.47 g, 3.0 mmol) and1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.6 g, 2.4 mmol)were dissolved in acetonitrile (15 mL). Potassium carbonate (0.66 g, 4.8mmol) was then added and the reaction mixture was stirred at roomtemperature under nitrogen atmosphere for 18 hours. The reaction mixturewas partitioned with water and diethyl ether. The organic layer waswashed with brine, dried with Na₂SO₄, filtered and the solventevaporated in vacuo to yield a crude oil. The crude oil was purified viaflash chromatography (30-50% ethyl acetate/hexane) to yield the titlecompound as an oil.

¹H NMR (300 MHz, CDCl₃) δ7.03-6.93 (4H, m), 6.46 (1H, br s), 4.67 (2H,s), 2.82-2.69 (4H, m), 2.48 (2H, q), 2.31-2.21 (2H, m), 1.81-1.76 (2H,m), 1.08 (3H, t) MS (ES⁺) m/z 278.2 (M+H)⁺.

EXAMPLE 418-(4-Chloro-benzyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #508

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (3.0 g, 12.03mmol) and 4-chloro-benzaldehyde (2.03 g, 14.44 mmol) were dissolved indry tetrahydrofuran (120 mL). To the reaction mixture was then added at0° C. sodium triacetoxyborohydride (3.82 g, 18.05 mmol) under nitrogenatmosphere and the reaction mixture was stirred at room temperature for18 hours. The reaction mixture was then partitioned with 1N NaOH andethyl acetate. The organic layer was washed with brine, dried withNa₂SO₄, filtered and the solvent evaporated in vacuo to yield a crudeoil. The crude oil was purified via flash chromatography (3.5%methanol/dichloromethane) to yield the title compound as a white foam.

¹H NMR (300 MHz, CDCl₃) δ7.30-7.15 (4H, m), 7.01-6.87 (4H, m), 4.63 (2H,s), 3.47 (2H, s), 2.78-2.65 (4H, m), 2.31-2.0 (2H, m), 1.73-1.68 (2H, m)MS (ES⁺) m/z 374.1 (M+H)⁺.

EXAMPLE 428-(4-Chloro-benzyl)-1-(4-fluoro-phenyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #513

8-(4-Chloro-benzyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one(0.220 g, 0.588 mmol) was dissolved in N,N-dimethylformamide (2.2 mL).To the reaction mixture was then added at 0° C. sodium hydride (60% inmineral oil, 31 mg, 0.765 mmol) under nitrogen atmosphere and thereaction mixture was stirred at 0° C. for 40 minutes. To the reactionmixture was then added (S)-epichlorhydrin (0.14 mL, 1.765 mmol) at 0° C.The reaction mixture was stirred at room temperature under nitrogenatmosphere for 18 hours and partitioned with water and ethyl acetate.The organic layer was washed with brine, dried with Na₂SO₄, filtered andthe solvent evaporated in vacuo to yield a crude oil. The crude oil waspurified via flash chromatography (2% methanol/dichloromethane) to yieldthe title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ7.32-7.26 (4H, m), 7.04-6.91 (4H, m), 4.77 (H,d, J=4.9Hz), 4.66 (1H, d, J=4.9Hz), 4.06-3.99 (1H, m), 3.52 (3H, s),3.20-3.14 (2H, m), 2.85-2.68 (5H, m), 2.60-2.58 (1H, m), 2.33-2.23 (2H,m), 1.73-1.60 (2H, m) MS (ES⁺) m/z 430.2 (M+H)⁺.

EXAMPLE 431-(4-Fluoro-phenyl)-3-(S)-[2-hydroxy-3-(2-morpholin-4-1-ethylamino)-propyl]-8-(5-phenyl-thien-2-yl-methyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #293

(R)-1-(4-Fluoro-phenyl)-3-oxiranylmethyl-8-(5-phenyl-thien-2-yl-methyl)-1,3,8-triaza-spiro[4.5]decan-4-one(0.02 g, 0.041 mmol) was dissolved in absolute ethanol (1 mL), mixedwith 2-morpholin-4-yl-ethylamine (16.3 mg, 0.125 mmol) and heated understirring at 70° C. overnight. The solvent was evaporated and theresulting residue was purified via flash chromatography (9%methanol/dichloromethane) to yield the title compound as an oil.

¹H NMR (300 MHz, CDCl₃) δ7.59-7.56 (2H, m), 7.38-7.33 (2H, m), 7.28-7.25(2H, m), 7.14 (1H, d, J=3.6 Hz), 7.04-6.91 (3H, m), 6.87 (1H, d, J=3.5Hz), 4.80-4.76 (2H, m), 3.86-3.69 (6H, m), 3.61-3.55 (1H, m), 3.36-3.29(1H, m), 2.85-2.71 (7H, m), 2.58-2.32 (1OH, m), 1.72 (2H, d, J=13.7 Hz)MS (ES⁺) m/z 608.3 (M+H)⁺.

EXAMPLE 441-(4-Fluoro-phenyl)-8-quinoline-8-ylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #522

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.15 g, 0.601mmol) and quinoline-8-carbaldehyde (0.113 g, 0.722 mmol) were dissolvedin dry tetrahydrofuran (12 mL). To the reaction mixture was then addedat 0° C. sodium triacetoxyborohydride (0.192 g, 0.902 mmol) undernitrogen atmosphere and the reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was then partitioned with1N NaOH and ethyl acetate. The organic layer was washed with brine,dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yielda crude oil. The crude oil was purified via flash chromatography (5%methanol/dichloromethane) to yield the title compound as a white solid.

¹H NMR (300 MHz, CDCl₃) δ8.93-8.91 (1H, m), 8.14 (1H, d, J=8.3 Hz), 7.89(1H, br s), 7.71 (1H, m), 7.55 (1H, t, J=7.7 Hz), 7.41-7.38 (1H, m),7.05-7.01 (4H, m), 6.79 (1H, br s), 4.69 (2H, s), 4.35 (2H, s),3.01-2.90 (4H, m), 2.41 (2H, br s), 1.80 (2H, d, J=13.8 Hz) MS (ES⁺) m/z391.0 (M+H)⁺.

EXAMPLE 45(R)-8-Acenaphthen-1-yl-3-(R)-(3-ethoxy-2-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #571

(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(R)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.084 g, 0.183 mmol) was dissolved in ethanol (4 mL). The reactionmixture was heated at 80° C. for 18 hours, then cooled to roomtemperature and the solvent evaporated in vacuo to yield an oil. The oilwas partitioned with water and ethyl acetate. The organic layer wasdried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yielda crude oil. The crude oil was purified via flash chromatography (4%[methanol in ammonia 2.0M]/dichloromethane) to yield the title compoundas an oil.

¹H NMR (300 MHz, CDCl₃) δ7.69-7.66 (1H, m), 7.61 (1H, d, J=8.2 Hz),7.54-7.50 (2H, m), 7.44 (1H, t), 7.27-7.25 (1H, m), 7.05-6.90 (4H, m),4.98-4.90 (1H, m), 4.77-4.71 (2H, m), 4.03-3.98 (1H, m), 3.57-3.31 (8H,m), 3.16-3.01 (3H, m), 2.88-2.85 (1H, m), 2.43 (2H, br s), 2.32-2.24(1H, m), 1.77-1.62 (2H, m), 1.18 (3H, t); MS (ES⁺) m/z 504.3 (M+H)⁺.

EXAMPLE 463-[3-(Ethyl-methyl-amino)-2-hydroxy-(S)-propyl]-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #440

1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(R)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.02 g, 0.043 mmol) was dissolved in ethyl alcohol (2 mL). To thesolution was then added N-methylethylamine (0.2 mL) and the reactionmixture was stirred at 40° C. for 3 hrs in a pressure flask. The solventwas then evaporated in vacuo to yield a crude oil. The crude oil waspurified via flash chromatography (5.0% ammonia 2.0 M inmethanol/dichloromethane) to yield the title compound as an oil.

¹H NMR (400 MHz, CDCl₃) δ7.77-7.75 (1H, m), 7.71-7.68 (1H, m), 7.38-7.30(4H, m), 6.96-6.91 (2H, m), 6.88-6.84 (2H, m), 4.82-4.75 (2H, m),4.08-3.98 (3H, m), 3.61-3.57 (1H, m), 3.34-3.29 (1H, m), 3.11 (3H, s),2.83-2.54 (8H, m), 2.44 (3H, s), 2.32-2.23 (2H, m), 1.68-1.63 (2H, m);1.15 (3H, t, J=7.2 Hz) MS (ES⁺) m/z 519.3 (M+H)⁺.

EXAMPLE 47(R)-Acenaphthen-1-yl-3-(3-dimethylamino-2-hydroxy-(R)-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #423

(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one (0.057 g, 0.124 mmol)was dissolved in ethyl alcohol (2 mL). To the solution was then added asolution of 2.0M dimethylamine in THF (1 mL) and the reaction mixturewas stirred at 40° C. for 2.5 hrs in a pressure flask. The solvent wasthen evaporated in vacuo to yield a crude oil. The crude oil waspurified via flash chromatography (6.0% ammonia 2.0 M inmethanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ7.68-7.65 (1H, m), 7.59 (1H, d, J=8.2 Hz),7.52-7.49 (2H, m), 7.44 (1H, t), 7.26-7.25 (1H, m), 7.03-6.94 (4H, m),4.97-4.94 (1H, m), 4.83-4.80 (2H, m), 4.77-4.75 (1H, m), 3.87-3.81 (1H,m), 3.60-3.03 (7H, m), 2.85-2.82 (1H, m), 2.49-2.42 (2H, m), 2.32-2.24(8H, m), 1.75-1.62 (2H, m) MS (ES⁺) m/z 503.3 (M+H)⁺.

EXAMPLE 481-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #550

1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one(2.0 g, 4.95 mmol) was dissolved in N,N-dimethylformamide (25.0 mL). Tothe reaction mixture was then added at 0° C. sodium hydride (60% inmineral oil, 238 mg, 5.94 mmol) under nitrogen atmosphere and thereaction mixture was stirred at 0° C. for one hour. To the reactionmixture was then added at 0° C.(2R)-(−)-glycidyl-3-nitrobenzenesulfonate (1.54 g, 5.94 mmol). Thereaction mixture was stirred at 0° C. for one hour, then at roomtemperature under nitrogen atmosphere for 18 hours and partitioned withwater and ethyl acetate. The organic layer was washed with brine, driedwith Na₂SO₄, filtered and the solvent evaporated in vacuo to yield acrude oil. The crude oil was purified via flash chromatography (2.5%methanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ7.78-7.76 (1H, m), 7.73-7.69 (1H, m), 7.38-7.31(4H, m), 6.99-6.91 (2H, m), 6.89-6.84 (2H, m), 4.76 (1H, d, J=4.8 Hz),4.65 (1H, d, J=4.8 Hz), 4.01 (2H, s), 3.20-3.11 (6H, m), 2.86-2.77 (5H,m), 2.61-2.59 (1H, m), 2.31-2.21 (2H, m), 1.69-1.63 (2H, m) MS (ES⁺) m/z460.2 (M+H)⁺.

EXAMPLE 493,3,3-Trifluoro-N-{3-[1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl]-2-(R)-hydroxy-propyl}-2-methoxy-2-phenyl-(R)-propionamideCompound #615

3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one(0.0118 g, 0.024 mmol) was dissolved in dichloromethane (1.0 mL) andpyridine (0.15 mL). To the reaction mixture was then added at 0° C.(S)-(+)-α-methoxy-α-(trifluoro methyl)phenyl acetyl chloride (8.7 mg,0.034 mmol) under nitrogen atmosphere. The reaction mixture was stirredat 0° C. for one hour, then the solvent was evaporated in vacuo to yielda crude foam. The crude foam was dissolved in ethyl acetate andsuccessively washed twice with aqueous 0.5N HCl, twice with aqueousNaHCO₃, brine, dried with Na₂SO₄, filtered and the solvent evaporated invacuo to yield a white foam.

¹H NMR (300 MHz, CDCl₃) δ7.78-7.75 (1H, m), 7.71-7.68 (1H, m), 7.64-7.61(1H, m), 7.56-7.54 (2H, m), 7.42-7.40 (3H, m), 7.39-7.30 (3H, m),6.97-6.93 (2H, m), 6.87-6.83 (2H, m), 4.70 (1H, d, J=4.9 Hz), 4.64 (1H,d), J=4.9 Hz), 3.99 (3H, s), 4.01 (1H, s), 3.60-3.54 (1H, m), 3.45-3.32(5H, m), 3.1 (3H, s), 2.82-2.74 (4H, m), 2.24-2.20 (2H, m), 1.70-1.63(4H, m) MS (ES⁺) m/z 693.0 (M+H)⁺.

EXAMPLE 503-(3-Dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #441

1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.035 g, 0.07mmol) was dissolved in ethyl alcohol (2 mL). To thesolution was then added a 2.0M solution of dimethylamine in methanol(1.0 mL, 2.0 mmol) and the reaction mixture was stirred at 45° C. for 3hrs in a pressure flask. The solvent was then evaporated in vacuo toyield a crude oil. The crude oil was purified via flash chromatography(5.0% ammonia 2.0 M in methanol/dichloromethane) to yield the titlecompound as a foam.

¹H NMR (400 MHz, CDCl₃) δ7.78-7.75 (1H, m), 7.71-7.68 (1H, m), 7.38-7.31(4H, m), 6.96-6.91 (2H, m), 6.88-6.84 (2H, m), 4.80 (1H, d, J=5.1 Hz),4.77 (1H, d, J=5.1 Hz), 4.01 (2H, m), 3.95-3.87 (1H, m), 3.62-3.58 (1H,m), 3.31-3.26 (1H, m), 3.11 (3H, s), 2.86-2.78 (6H, m), 2.36-2.22 (9H,m), 1.68-1.63 (2H, m). MS (ES⁺) m/z 505.4 (M+H)⁺.

EXAMPLE 511-(4-Fluoro-phenyl)-3-(2-(R)-hydroxy-3-methylamino-propyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #660

1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.05 g, 0.109 mmol) was dissolved in methanol (3 mL). To the solutionwas then added a 2.0M solution of methylamine in methanol (1.0 mL, 2.0mmol) and the reaction mixture was stirred at 40° C. for 3 hrs in apressure flask. The solvent was then evaporated in vacuo to yield acrude oil. The crude oil was purified via flash chromatography (5.0%ammonia 2.0 M in methanol/dichloromethane) to yield the title compoundas a foam.

¹H NMR (400 MHz, CDCl₃) δ7.78-7.75 (1H, m), 7.71-7.68 (1H, m), 7.38-7.31(4H, m), 6.96-6.91 (2H, m), 6.88-6.84 (2H, m), 4.80 (1H, d, J=5.1 Hz),4.77 (1H, d, J=5.1 Hz), 4.00 (2H, m), 3.97-3.86 (1H, m), 3.58-3.53 (1H,m), 3.43-3.35 (1H, m), 3.12 (3H, s), 2.84-2.69 (7H, m), 2.56-2.49 (1H,m), 2.44 (3H, s), 2.31-2.24 (2H, m), 1.67-1.64 (2H, m) MS (ES⁺) m/z491.1 (M+H)⁺.

EXAMPLE 521-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-methylamino-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #656

1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.035 g, 0.07 mmol) was dissolved in methanol (4 mL). To the solutionwas then added N-methyl-1-3-propanediamine (0.027 g, 0.35 mmol) and thereaction mixture was stirred at 45° C. for 12 hrs in a pressure flask.The solvent was then evaporated in vacuo to yield a crude oil. The crudeoil was purified via flash chromatography (5.0% ammonia 2.0 M inmethanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ7.78-7.75 (1H, m), 7.71-7.68 (1H, m), 7.38-7.30(4H, m), 6.95-6.91 (2H, m), 6.87-6.84 (2H, m), 4.80 (1H, d, J=5.05 Hz),4.77 (1H, d, J=5.05 Hz), 4.00 (2H, s), 3.96-3.89 (1H, m), 3.58-3.54 (1H,m), 3.32-3.30 (1H, m), 3.12 (3H, s), 2.85-2.77 (6H, m), 2.65-2.58 (1H,m), 2.49-2.12 (10H, m), 1.68-1.63 (4H, m) MS (ES⁺) m/z 548.3 (M+H)⁺.

EXAMPLE 533-[3-(3-Dimethylamino-propylamino)-2-(R)-hydroxy-propyl]-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #666

1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.037 g, 0.07 mmol) was dissolved in ethanol (2 mL). To the solutionwas then added dimethylaminopropylamine (0.03 g, 0.3 mmol) and thereaction mixture was stirred at 45° C. for 12 hrs in a pressure flask.The solvent was then evaporated in vacuo to yield a crude oil. The crudeoil was purified via flash chromatography (5.0% ammonia 2.0 M inmethanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ7.78-7.75 (1H, m), 7.71-7.68 (1H, m), 7.38-7.30(4H, m), 6.97-6.90 (2H, m), 6.87-6.82 (2H, m), 4.78-4.73 (2H, m), 4.00(2H, s), 3.96-3.82 (1H, m), 3.59-3.53 (1H, m), 3.37-3.30 (1H, m), 3.12(3H, s), 2.86-2.50 (9H, m), 2.35-2.11 (11H, m), 1.68-1.59 (4H, m) MS(ES⁺) m/z 562.2 (M+H)⁺.

EXAMPLE 541-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-hydroxy-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #651

1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(1.16 g, 2.5 mmol) was dissolved in methanol (20 mL). To the solutionwas then added 3-amino-1-propanol (0.375 g, 5.0 mmol,) and the reactionmixture was stirred at 40° C. for 12 hrs in a pressure flask. Thesolvent was then evaporated in vacuo to yield a crude oil. The crude oilwas purified via flash chromatography (5.0% ammonia 2.0 M inmethanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (300 MHz, CDCl₃) δ7.78-7.75 (1H, m), 7.71-7.68 (1H, m), 7.38-7.30(4H, m), 6.97-6.90 (2H, m), 6.87-6.82 (2H, m), 4.74-4.70 (2H, m), 3.99(2H, s), 3.96-3.90 (1H, m), 3.81-3.77 (2H, m), 3.47-3.42 (3H, m), 3.11(3H, s), 2.91-2.56 (10H, m), 2.30-2.20 (2H, m), 1.76-1.63 (4H, m) MS(ES⁺) m/z 535.2 (M+H)⁺.

EXAMPLE 5511-(4-Fluoro-phenyl)-8-(8-methyl-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #728

Step A:

8-Methyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (J. Org. Chem.1982, 47, 2590-2593) (0.066 g, 0.34 mmol) was dissolved intetrahydrofuran (3 mL). To the solution was then added at 0° C. a 1.0Msolution of borane-methyl sulfide complex in dichloromethane (0.7 mL,0.69 mmol). The reaction mixture was stirred at room temperature for 15minutes, refluxed for 2 hrs, then cooled down to 0° C. and quenched withmethanol. The solvent was then evaporated in vacuo to yield a crude oil.The crude oil was partitioned with water and diethyl ether. The organiclayer was dried with Na₂SO₄, filtered and the solvent evaporated invacuo to yield crude(8-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol as an oil whichwas used directly to the next step.

¹H NMR (400 MHz, CDCl₃) δ 7.05-6.92 (3H, m), 3.70-3.59 (2H, m),3.15-3.10 (1H, m), 2.83-2.71 (2H, m), 2.34 (3H, s), 2.21-2.16 (1H, m),1.95-1.83 (1H, m), 1.79.1.67 (2H, m), 1.52 (1H, br s)

Step B:

(8-Methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol (0.03 g, 0.17mmol) was dissolved in dichloromethane (0.5 mL). To the solution wasthen added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, alsoknown as Dess-Martin periodinane (0.087 g, 0.20 mmol). The reactionmixture was stirred for 2 hrs then partitioned with an aqueous saturatedsolution of thiosulfate and dichloromethane. The organic layer waswashed with an aqueous saturated solution of thiosulfate, an aqueoussaturated solution of sodium bicarbonate, brine, dried with Na₂SO₄,filtered and the solvent evaporated in vacuo to yield8-methyl-1,2,3,4-tetrahydro-naphthalene-1-carbaldehyde as a solid.

¹H NMR (400 MHz, CDCl₃) δ 9.66 (1H, d, J=1.8 Hz), 7.13-6.99 (3H, m),3.74-3.72 (1H, m), 2.81-2.77 (2H, m), 2.37-2.31 (1H, m), 2.2 (3H, s),1.95-1.61 (3H, m).

Step C:

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.035 g, 0.14mmol) and 8-methyl-1,2,3,4-tetrahydro-naphthalene-1-carbaldehyde (0.03g, 0.17 mmol) were dissolved in dry tetrahydrofuran (2 mL) and drydichloromethane (0.5 mL). To the reaction mixture was then added at 0°C. sodium triacetoxyborohydride (0.045 g, 0.21 mmol) under nitrogenatmosphere and the reaction mixture was stirred at room temperature for18 hours. The reaction mixture was then partitioned with 1N NaOH andethyl acetate. The organic layer was washed with brine, dried withNa₂SO₄, filtered and the solvent evaporated in vacuo to yield a crudeoil. The crude oil was purified via flash chromatography (5%methanol/dichloromethane) to yield the title compound as an oil.

¹H NMR (400 MHz, CDCl₃) δ 7.06-6.90 (7H, m), 6.56 (1H, br s), 4.68 (2H,s), 3.12-2.33 (12H, m), 1.91-1.53 (6H, m), 1.25-1.21 (2H, m) MS (ES⁺)m/z 408.1 (M+H)⁺.

EXAMPLE 56(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-hydroxy-3-(3-hydroxymethyl-piperidin-1-yl)-(R)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #695

(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.02 g, 0.04 mmol) was dissolved in ethyl alcohol (1.5 mL). To thesolution was then added 3-piperidinemethanol (0.01 g, 0.08 mmol) and thereaction mixture was stirred at 60° C. for 12 hrs in a pressure flask.The solvent was evaporated in vacuo to yield a crude oil. The crude oilwas purified via flash chromatography (6.0% ammonia 2.0 M inmethanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ7.69-7.49 (4H, m), 7.46-7.41 (1H, m), 7.26-7.25(1H, m), 7.04-6.95 (4H, m), 4.97-4.94 (1H, m), 4.81-4.74 (2H, m),3.97-3.90 (1H, m), 3.58-1.6 (27H, m) MS (ES⁺) m/z 573.3 (M+H)⁺.

EXAMPLE 57N-{3-[(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-3-yl]-2-hydroxy-(R)-propyl}-3,3,3-trifluoro-2-methoxy-2-phenyl-(R)-propionamideCompound #645

(R)-8-Acenaphthen-1-yl-3-(3-amino-2-hydroxy-(R)-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one(0.02 g, 0.042 mmol) was dissolved in dichloromethane (3 mL) andpyridine (0.3 mL). To the reaction mixture was then added at 0° C.(S)-(+)-(α-methoxy-(α-(trifluoromethyl)phenyl acetyl chloride (13.8 mg,0.055 mmol) under nitrogen atmosphere. The reaction mixture was stirredat 0° C. for one hour, then and the solvent evaporated in vacuo to yielda crude foam. The crude foam was dissolved in ethyl acetate andsuccessively washed twice with aqueous 0.5N HCl, twice with aqueousNaHCO₃, brine, dried with Na₂SO₄, filtered and the solvent evaporated invacuo to yield the title compounds as a white foam.

¹H NMR (400 MHz, CDCl₃) δ7.68-7.59 (3H, m), 7.55-7.39 (8H, m), 7.03-6.99(2H, m), 6.98-6.93 (2H, m), 4.95-4.92 (1H, m), 4.70 (1H, d, J=4.8 Hz),4.65 (1H, d, J=4.9 Hz), 3.99-3.97 (1H, s), 3.76 (1H, s), 3.57-3.29 (5H,m), 3.08-3.00 (2H, m), 2.79-2.76 (1H, m), 2.46-2.37 (1H, m), 2.37-2.29(1H, m), 2.24-2.16 (1H, m), 2.00 (3H, s), 1.74-1.60 (4H, m) MS (ES⁺) m/z691.3 (M+H)⁺.

EXAMPLE 581-(4-Fluoro-phenyl)-8-(8-hydroxymethyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #734

Step A:

[8-(tert-Butyl-dimethyl-silanyloxymethyl)-naphthalen-1-yl]-methanol(Aust. J. Chem. 1996, 49, 793-800) (0.2 g, 0.66 mmol) was dissolved indichloromethane (8 mL). To the solution was then added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, also known asDess-Martin periodinane (0.56 g, 1.32 mmol). The reaction mixture wasstirred for 1 hr then partitioned with an aqueous saturated solution ofthiosulfate and dichloromethane. The organic layer was washed with anaqueous saturated solution of thiosulfate, an aqueous saturated solutionof sodium bicarbonate, brine, dried with Na₂SO₄, filtered and thesolvent evaporated in vacuo to yield a crude oil. The crude oil waspurified via flash chromatography (6.0% ammonia 2.0 M inmethanol/dichloromethane) to yield8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalene-1-carbaldehyde as aclear oil.

¹H NMR (400 MHz, CDCl₃) δ 10.73 (1H, s), 8.05-7.98 (2H, m), 7.86-7.84(1H, m), 7.65-7.63 (1H, m), 7.55-7.48 (2H, m), 5.07 (2H, s), 0.83 (9H,s), 0.01 (6H, s)

Step B:

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.056 g, 0.22mmol) and8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalene-1-carbaldehyde(0.067 g, 0.22 mmol) were dissolved in dry 1,2-dichloroethane (5 mL). Tothe reaction mixture was added crashed 4A Molecular Sieve (0.028 g), acatalytic amount of glacial acetic acid. The reaction mixture wasstirred at room temperature for 1 hr and it was then added at roomtemperature sodium triacetoxyborohydride (0.071 g, 0.33 mmol) undernitrogen atmosphere and the reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was then partitioned withwater and dichloromethane. The organic layer was washed with brine,dried with Na₂SO₄, filtered and the solvent evaporated in vacuo to yielda crude oil. The crude oil was purified via semi-preparative HPLC(aqueous 0.5% TFA/acetonitrile) to yield crude8-[8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalen-1-ylmethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-onewhich was directly used to the next step.

Step C:

To the crude intermediate prepared as in STEP B was added acetonitrile(5 mL) and aqueous 5% TFA (5 mL). The reaction mixture was stirred atroom temperature for 6 hrs. The solvent was then evaporated in vacuo toyield the title compound as a solid.

¹H NMR (400 MHz, CDCl₃) δ 8.85 (1H, br s), 7.86-7.81 (2H, m), 7.53-7.51(1H, m), 7.43-7.33 (3H, m), 6.98-6.92 (2H, m), 6.84-6.79 (2H, m), 6.55(1H, s), 5.12 (2H, br s), 4.66 (2H, s), 4.33 (1H, br s), 3.03-2.93 (4H,m), 2.38-2.31 (2H, m), 1.79-1.75 (2H, m) MS (ES⁺) m/z 420.1 (M+H)⁺.

EXAMPLE 591-(4-Fluoro-phenyl)-8-(8-methoxymethyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #733

Step A:

(8-Methoxymethyl-naphthalen-1-yl)-methanol (Tetrahedron Lett. 1997; 38,8161-8164) (0.36 g, 1.8 mmol) was dissolved in dichloromethane (10 mL).To the solution was then added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, also known asDess-Martin periodinane (1.5 g, 3.6 mmol). The reaction mixture wasstirred for 1 hr, then partitioned with an aqueous saturated solution ofthiosulfate and dichloromethane. The organic layer was washed with anaqueous saturated solution of thiosulfate, an aqueous saturated solutionof sodium bicarbonate, brine, dried with Na₂SO₄, filtered and thesolvent evaporated in vacuo to yield crude8-methoxymethyl-naphthalene-1-carbaldehyde which was used directly intothe next step.

Step B:

1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.45 g, 1.8mmol) and crude 8-methoxymethyl-naphthalene-1-carbaldehyde (0.35 g, 1.8mmol) were dissolved in dry dichloromethane (25 mL), dry1,2-dichloroethane (5 mL) and glacial acetic acid (0.5 mL). The reactionmixture was stirred at room temperature for 1 hr. To the reactionmixture was then added, at room temperature, sodiumtriacetoxyborohydride (0.57 g, 2.7 mmol) under nitrogen atmosphere andthe reaction mixture was stirred at room temperature for 4 days. Thereaction mixture was partitioned with water and dichloromethane. Theorganic layer was washed with brine, dried with Na₂SO₄, filtered and thesolvent evaporated in vacuo to yield a crude oil. The crude oil waspurified via flash chromatography (40% ethyl acetate in hexanes) toyield the title compound as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.85-7.80 (2H, m), 7.60-7.58 (1H, m),7.49-7.37 (3H, m), 6.94-6.83 (4H, m), 6.12 (1H, s), 5.23 (2H, s), 4.64(2H, s), 4.10 (2H, s), 3.38 (3H, s), 2.91-2.81 (4H, m), 2.30-2.23 (2H,m), 1.73-1.70 (2H, m) MS (ES⁺) m/z 434.2 (M+H)⁺.

EXAMPLE 60(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(2-(R)--oxiranyl-ethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #723

(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one(0.25 g, 0.62 mmol) was dissolved in N,N-dimethylformamide (2.0 mL). Tothe reaction mixture was then added at 0° C. sodium hydride (60% inmineral oil, 0.03 g, 0.80 mmol) under nitrogen atmosphere. The reactionmixture was stirred at 0° C. for 30 minutes. To the reaction mixture wasthen added, at 0° C., 2-(R)-(2-bromo-ethyl)-oxirane (0.14 g, 0.93 mmol).The reaction mixture was stirred at 0° C. under nitrogen atmosphere for1 hr, then room temperature for 18 hours and then partitioned with waterand ethyl acetate. The organic layer was dried with Na₂SO₄, filtered andthe solvent evaporated in vacuo to yield a crude oil. The crude oil waspurified via flash chromatography (6% methanol/dichloromethane) to yieldthe title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ7.70-7.65 (1H, m), 7.59 (1H, d, J=8.2 Hz),7.54-7.50 (2H, m), 7.43 (1H, t), 7.26 (1H, d), 7.04-6.93 (4H, m), 4.95(1H, dd, J=3.4 and 7.8 Hz), 4.64 (2H, dd, J=4.3 and 10.7 Hz), 3.64-3.50(3H, m), 3.38-3.31 (1H, m), 3.19-3.03 (2H, m), 2.97-2.92 (1H, m),2.83-2.80 (1H, m), 2.75-2.73 (1H, m), 2.48-2.39 (3H, m), 2.29-2.21 (1H,m), 2.03-1.95 (1H, m), 1.75-1.62 (3H, m) MS (ES⁺) m/z 472.2 (M+H)⁺.

EXAMPLE 61(R)-8-Acenaphthen-1-yl-3-(4-amino-3-(S)-hydroxy-butyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #722

(R)-8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(2-(R)-(oxiranyl-ethyl)-1,3,8-triaza-spiro[4.5]decan-4-one(0.03 g, 0.06 mmol) was dissolved in ethyl alcohol (1.0 mL). To thesolution was then added concentrated ammonium hydroxide (1.0 mL) and thereaction mixture was stirred at 40° C. for 7 hrs in a pressure flask.The solvent was then evaporated in vacuo to yield a crude oil. The crudeoil was purified via flash chromatography (6.0% ammonia 2.0 M inmethanol/dichloromethane) to yield the title compound as a foam.

¹H NMR (400 MHz, CDCl₃) δ7.70-7.65 (1H, m), 7.59 (1H, d, J=8.2 Hz),7.54-7.50 (2H, m), 7.43 (1H, t), 7.26 (1H, d), 7.04-6.93 (4H, m),4.96-4.94 (1H, m), 4.64 (2H, dd, J=4.3 and 10.7 Hz), 3.86-3.76 (1H, m),3.57-3.45 (2H, m), 3.39-2.98 (4H, m), 2.85-2.76 (2H, m), 2.65-2.58 (1H,m), 2.52-2.40 (2H, m), 2.32-2.24 (1H, m), 2.10-1.90 (3H, m), 1.76-1.51(4H, m) MS (ES⁺) m/z 489.1 (M+H)⁺.

EXAMPLE 628-(S)-Acetonaphthen-1-yl-1-(4-fluoro-phenyl)-3-[2-(R)-hydroxy-3-(1-phenyl-ethylamino)-propyl]-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #663

8-Acenaphthen-1-yl-1-(4-fluoro-phenyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.45 g, 0.98 mmol) and R-(+)-α-methylbenzyl amine (0.178 g, 1.47 mmol)were dissolved in ethanol (3 mL). The reaction mixture was heated at120° C. and microwaved for 600 sec. The solvent was evaporated in vacuoto yield an oil. The crude oil was purified via flash chromatography(80% ethyl acetate/heptane) to yield the title compound as a solid.

¹H NMR (300 MHz, CDCl₃) δ 7.65 (1H, t), 7.60 (1H, d, J=8.2 Hz),7.50-7.54 (2H, d, J=5.1 Hz), 7.44 (1H, t), 7.07-7.28 (6H, m), 6.8-7.0(4H, m), 4.9 (1H, m), 4.6 (2H, s), 3.8 (2H, m), 3.25-3.55 (5H, m),2.95-3.1 (2H, m), 2.78-2.82 (1H, m), 2.6 (1H, m), 2.1-2.4 (5H, m), 1.5(2H, m), 1.3 (3H, d) MS (ES⁺) m/z 579.2 (MH+), 427.2

EXAMPLE 633-(3-Amino-2-(R)-hydroxy-propyl)-8-cyclooctylmethyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-oneCompound #620

Cyclooctylmethyl-1-(4-fluoro-phenyl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(0.71 g, 1.65 mmol) was dissolved in absolute ethanol (5 mL), then mixedwith ammonium hydroxide (2 mL, 14.4 mmol) and heated to 120° C. andmicrowaved for 600 sec. The solvent was evaporated and the resultingresidue was purified by column chromatography (80% ethylacetate/heptane) to yield the title compound as an oil.

MS (electrospray)=447.4 (MH+) ¹H NMR (300 MHz, CDCl₃) δ 1.1-1.3 (m, 2H),1.4-1.8 (m, 16 H), 2.1 (d, 2H), 2.2-2.38 (m, 2H), 2.6-2.8 (m, 5H),2.8-3.0 (m, 2H), 3.3-3.6 (m, 2H), 3.7-3.8 (m, 2H), 4.7 (s, 2H), 6.8-7.0(m, 4H).

EXAMPLE 643-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1,3,8-triaza-spiro[4.5]decan-4-onedihydrochloride Compound #640

1-(4-Fluoro-phenyl)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-3-(S)-oxiranylmethyl-1,3,8-triaza-spiro[4.5]decan-4-one(60 mg, 0.131 mmol) was dissolved in absolute ethanol (1 mL), then mixedwith ammonium hydroxide (0.3 mL) and heated to 120° C. and microwavedfor 480 sec. The solvent was evaporated. The resulting residue wasdissolved in ethyl acetate and then treated with HCl in diethyl ether(1M, 1 mL) to yield the title compound as a solid.

MS (electrospray)=475.2 (MH+), 305.1 ¹H NMR (300 MHz, CD₃OD) δ 0.9-1.0(m, 1H), 1.1-1.5 (m, 5H) 1.7-1.8 (m, 1H), 2.0-2.25 (m, 6H), 2.3-2.7 (m,4H), 2.7-3.2 (m, 7H), 3.32-3.7 (m, 2H), 3.85-4.2 (m, 2H), 4.9 (m, 2H),6.9-7.4 (m, 8H)

EXAMPLE 651-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-oneCompound #547

Step A: (8-Hydroxymethyl-naphthalen-1-yl)-methanol

A 12-L 4-neck flask equipped with a thermocouple, an overhead stirrer, a2-L addition funnel, and a condenser under N₂ was charged with1,8-naphthalic anhydride (200 g, 1.0 mol) in toluene (2.5 L) at roomtemperature. The reaction mixture was agitated while adding DIBAL-H (1.5M in toluene, 2.664 L, 4 mol) via the addition funnel over 1.5 h. Thesolution was then heated to 95° C. overnight, cooled to 15° C. and thenslowly diluted with ethyl acetate (2.2 L) and H₂O (2 L) followed byaddition of concentrated HCl (320 mL). The resulting suspension wasstirred for 30 min at room temperature, filtered, and air dried on thefilter for 2 h. The resultant material was in 95% ethanol (1.2 L),stirred at 70° C. for 2 h, and filtered to yield a wet solid which wasair dried overnight on the filter and then dried at 70° C. in a vacuumoven to yield (8-hydroxymethyl-naphthalen-1-yl)-methanol as a solid;

¹H NMR (400 MHz, CD₃OD) δ7.85 (2H, dd, J=1.3 and 8.2 Hz), 7.61 (2H, dd,J=1.0 and 7.0 Hz), 7.46-7.42 (2H, m), 5.22 (2H, s), 4.82 (4H, s).

Step B: 1H,3H-Benzo[de]isochromene

A 1-L 3-neck flask equipped with an overhead stirrer, a condenser, and athermocouple was charged with (8-hydroxymethyl-naphthalen-1-yl)-methanol(33.0 g, 0.175 mol), concentrated phosphoric acid (225 mL), and water (5mL). The reaction mixture was stirred at 140° C. for 3 h, cooled to roomtemperature, diluted with CH₂Cl₂ (800 mL) and transferred to a 2-Lseparatory funnel. After washing the organic layer with water andsaturated NaHCO₃ it was dried over MgSO₄ and evaporated to yield1H,3H-Benzo[de]isochromene as a solid.

¹H NMR (400 MHz, DMSO-d₆): δ 6.96-6.92 (2H, m), 6.62-6.58 (2H, m),6.39-6.37 (2H, m), 4.17 (3H, s).

Step C: (8-Methyl-naphthalen-1-yl)-methanol (See Tetrahedron, 2000, 56,8375-8382)

A 3-L 4-neck flask equipped with an overhead stirrer, a thermocouple, acondenser, a nitrogen inlet, and a 1-L addition funnel was charged withpotassium (30 g, 0.764 mol) and THF (1 L). The metal suspension washeated to 60° C. for 30 min and then stirred to room temperature. To thereaction mixture was then added naphthalene (2 g, 0.015 mol), thesuspension was stirred at room temperature for 10 min and then cooled to−20° C. to afford a blue suspension. A solution of1H,3H-Benzo[de]isochromene (26 g, 0.153 mol) in THF (500 ml) was slowlyadded via the addition funnel, with addition controlled so that thereaction temperature did not exceed −15° C. After stirring for 5 h at−20° C., the suspension was removed from the cooling bath, warmed withstirring to 0° C., and then allowed to stand without stirring (potassiummetal settling). The solution was decanted and the residual potassiumwas cooled and carefully decomposed with isopropyl alcohol (IPA) underN₂. The decanted solution was carefully treated with water (20 mL) undernitrogen and stirring was continued for 20 min. Additional water andether were added and the organic layer was separated. The aqueous layerwas extracted with CH₂Cl₂ and the combined organics were dried overMgSO₄ and condensed in vacuo to yield a crude material. The crudematerial was purified by flash chromatography (7.5/2.5 hexane/EtOAc) toyield 8-methyl-1-napthalenemethanol as a solid.

¹H NMR (300 MHz, DMSO-d₆): δ 7.82-7.80 (1H, m), 7.73-7.69 (1H, m),7.52-7.50 (1H, m), 7.41-7.32 (3H, m), 5.17 (2H, bs), 3.01 (3H, s).

Step D: 8-Methyl-naphthalene-1-carbaldehyde

A 1-L 4-neck equipped with an overhead stirrer, a condenser and athermocouple was charged with 8-methyl-1-napthalenemethanol (18.5 g,0.107 mol) in CH₂Cl₂ (500 mL) and stirred at room temperature under N₂.Solid Mn_((IV))O₂ (61 g, 0.7 mol) was carefully added and the reactionwas stirred at room temperature for 3 h, then at 40° C. for 6 h and thenat room temperature overnight. The reaction mixture was diluted withCH₂Cl₂ (500 mL), filtered and the filtrate was washed with 1N HCl andthen dried over MgSO₄. The resulting crude material was purified usingsilica gel chromatography (8/2 hexane/ethyl acetate) to yield8-methyl-naphthalene-1-carbaldehyde as a solid.

¹H NMR (400 MHz, CDCl₃) δ 10.92 (1H, s), 8.04 (1H, dd, J=1.3 and 8.1Hz), 7.96 (1H, dd, J=1.4 and 7.1 Hz), 7.82-7.73 (1H, m), 7.55-7.51 (1H,m), 7.49-7.44 (2H, m), 2.82 (3H, s)

Step E:1-(4-Fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-one.

A 1-L 3-neck flask equipped with an overhead stirrer and a thermocouplewas charged with 8-methyl-naphthalene-1-carbaldehyde (13.75 g, 0.08 mol)and 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (21.5 g,0.085 mol) under N₂ in CH₂Cl₂ (500 mL). After stirring for 20 min, HOAc(1 mL) was added followed by careful addition of solid NaBH(OAc)₃ (33.4g, 0.157 mol). The mixture was stirred for 16 h at room temperature(suspension becomes a solution). The reaction was then warmed at 50° C.for 2 h, cooled down to room temperature and then treated with 0.5 NNaOH (50 mL), stirred for 10 min and then diluted with CH₂Cl₂ (100 mL).The organic layer was isolated and dried over MgSO₄. The solvent wasevaporated to yield a residue, which was suspended in diethyl ether,stirred for 20 min, filtered and dried in a 60° C. vacuum oven to yield1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]-decan-4-oneas a white solid;

¹H NMR (400 MHz, CDCl₃) δ 7.79-7.76 (1H, m), 7.72-7.69 (1H, m),7.39-7.30 (4H, m), 6.98-6.92 (2H, m), 6.87-6.82 (2H, m), 6.24 (1H, brs), 4.66 (2H, s), 4.01 (2H, s), 3.12 (3H, s), 2.86-2.78 (4H, m),2.33-2.23 (2H, m), 1.72 (2H, d, J=14.1 Hz); MS (ES⁺) m/z 404.2 (M+H)⁺.Elemental Analysis Calculated: C: 69.26%, H: 7.06%, N: 11.34%, F: 3.91%,H₂O: 1.85%.

Measured: C: 68.96%, H: 6.83%, N: 11.38%, F: 4.00%, H₂O: 0.58%.

EXAMPLE 66 Production of Cells Expressing the ORL-1, Delta, Kappa or MuReceptor

HEK293 cells were transfected with nociceptin receptor (ORL-1, humanmRNA GenBank #AF348323) or any of the opioid receptor subtype delta (δ,human mRNA Genbank #U07882) kappa (κ, human mRNA Genbank #U17298) and mu(μ, human mRNA Genbank #L29301). The vector used was pCi-neo (G418selection). The transfections were performed with LipofectAMINE 2000(Life Technologies Cat. # 11668-019) using the following procedure.

The day before transfection, a 24 well plate was inoculated with 2×10⁵cells per well in 0.5 ml of normal growth medium (MEM+EBSS+NEAA+10%BCS). Two wells were prepared for each specialty along with a no DNAcontrol. For each well transfected, 0.8 μg of DNA was diluted into 50 μl(total volume) of OPTI-MEM I Reduced Serum Medium (Life TechnologiesCat. # 51985-034). For each well transfected, 2 μl of LipofectAMINE 2000(LF2000) was diluted into 50 μl (total volume) of OPTI-MEM I medium andincubated for 5 minutes at room temperature. The diluted DNA and LF2000were combined and incubated at room temperature for 20 minutes. Thegrowth medium was aspirated from each well and replaced with 1 ml ofOPTI-MEM I. A total of 100 μl of the DNA-LF2000 complexes were added toeach well and mixed with gentle swirling. The plate was incubated at 37°C., 5% CO₂ for 5 hours. The OPTI-MEM I medium was aspirated from eachtransfected well and replaced with 1 ml growth medium. The plate wasreturned to the incubator for 24 hours. The wells were trypsinized andcells added to 100 mm tissue culture dishes (2 dishes per well). Thedishes were incubated for 24 hours. The medium was aspirated from eachdish and replaced with growth medium containing 400 μg/ml Geneticin(G418) selective antibiotic. The plates were refer every 3-4 days.

Distinct colonies appeared in approximately 3 weeks. One week later, 48out of approximately 100 colonies per dish were subcultures to 1 welleach of two 24 well plates containing 1 ml of selective medium per well.

Confluent wells were expanded to 6 well plates, then T25 flasks and T75flasks. Cell lines showing poor growth patterns were eliminated.Membranes were prepared from each cell line and receptor activitydetermined by a receptor binding assay.

EXAMPLE 67 Method for Measuring Affinity for the ORL-1 Receptor

The nociceptin receptor binding assay measures the binding of¹²⁵I-Tyr¹⁴-nociceptin (2200 Ci/mmol, New England Nuclear) to humannociceptin receptor (ORL-1) on HEK293 cell membranes.

HEK293 cell membrane (prepared as described in Pulito, V. L. et al.,2000, J. Pharmacol. Exp. Ther. 294, 224-229), with the exception thatthe buffer used was a mixture of 50 mM Tris-HCl pH7.8, 5 mM MgCl₂ and 1mM EGTA), was added to PEI treated WGA FlashPlates (New England Nuclear)at 1 μg/well in binding buffer of 50 mM Tris-HCl pH 7.8, 5 mM MgCl₂ and1 mM EGTA. ¹²⁵I-Tyr¹⁴-nociceptin was added at a final concentration of0.5 nM and the volume adjusted to 50 μl with binding buffer. The platewas incubated for two hours at room temperature, the reactions wereaspirated and the wells washed two times with 200 μl binding buffer andthen filled with 200 μl binding buffer. The plates were then sealed andcounted on a Packard Top Count to determine radioactivity bound to themembranes.

For each test compound, the total binding (% Inh) was measured atseveral concentrations and the IC₅₀ (the concentration at which 50% ofthe binding is inhibited) was determined from the graphical display ofX=logarithm of concentration versus Y=response, using the followingcalculation:

$Y = {({Minimum}) + \frac{\left( {{Maximum} - {Minimum}} \right)}{\left( {1 + 10^{\log{({{EC}_{50} - X})}}} \right)}}$

For some of the test compound, Ki was determined, using the followingcalculation:

Ki values were calculated using Graphpad Prizm software, whereKi=(IC₅₀)/(+[radioligand]/Kd)

For the ORL-1 binding, the Kd was 0.5 nM. The [radioligand] used was thesame as the Kd.

The ability of representative compounds of the present invention to bindto the ORL-1 receptor in a HEK cell line using a radio-labellednociceptin as the displaceable ligand was determine according to theprocedure described above with results as listed in Table 12. (Note thatfor the compounds which were tested more than once, the value listed inTable 12 is the calculated mean.)

TABLE 12 ID# ORL-1 IC₅₀ (nM) ORL-1 Ki (nM) 1 8.10 2 8.49 3 173.0 4 3.635 20.1 6 4.66 7 13.4 8 4.86 9 233.0 10 10.5 11 22.3 12 21.0 13 10.6 1425.2 15 31.8 16 122.0 17 10.8 18 10.3 19 15.0 20 15.8 21 9.22 22 20.7 2380.5 24 34.8 25 33.0 26 20.3 27 11.0 28 7.74 29 121.0 30 23.2 31 44.5 3213.7 33 95.3 34 26.9 35 30.3 36 8.73 38 8.88 39 149.0 40 9.40 41 8.32 4219.2 43 19.9 44 43.1 45 6.45 46 16.2 47 0.86 48 1.28 49 14.8 50 298.0 51259.0 52 0.48 53 0.47 54 3.03 55 2.75 56 4.70 57 20.0 58 476.0 59 94.560 396.0 61 1.09 62 0.78 63 19.2 64 33.9 65 88.5 66 39.2 67 12.2 68 10.469 20.5 70 72.9 71 59.3 72 82.6 73 14.0 74 8.08 75 21.1 76 16.1 78 18.079 18.2 100 4.10 101 1.79 102 199.0 103 18.5 104 0.72 105 81.6 106 55.4107 57.7 108 36.9 110 45.0 111 25.2 112 18.0 113 27.4 114 15.1 115 14.0116 17.0 117 99.7 119 2.8 121 39.9 122 32.4 123 61.2 124 41.6 125 44.1126 38.6 127 61.0 128 38.6 129 160.0 130 48.8 131 17.0 132 33.9 133108.0 134 329.0 135 17.3 136 1330.0 137 101.0 138 31.9 139 139.0 140108.0 141 26.0 142 49.9 143 39.7 144 40.0 145 12.8 146 85.6 147 34.3 14881.1 149 40.9 150 28.5 151 10.9 152 37.6 153 60.4 154 6.96 155 98.9 15621.8 157 43.5 158 41.9 159 298.0 160 53.5 161 90.7 162 46.0 163 539.0164 252.0 165 54.5 166 52.2 167 45.5 168 151.0 169 219.0 170 >10,000 17119.9 173 31.8 174 68.7 175 86.3 176 51.3 177 166.0 178 62.2 179 33.0 180116.0 181 67.3 182 7.7 183 40.0 187 17.1 188 7.1 189 7.6 190 41.0 19110.7 192 4.2 193 14.0 194 7.00 197 2.00 198 46.0 203 1.3 204 30.9 20517.5 206 8.0 208 10.7 209 33.00 210 3.10 211 2.90 215 9.35 217 12.7 2186.6 219 6.6 220 100.0 224 9.00 225 7.3 227 25.0 228 3.3 229 7.6 230105.0 250 59.7 251 10.5 252 35.2 253 20.4 254 16.3 255 66.5 256 23.5 25714.9 258 343.0 259 199.0 260 560.0 261 54.1 262 182.0 263 86.7 264 283.0265 366.0 266 471.0 267 178.0 268 147.0 269 157.0 270 148.0 271 0.70 2751.19 276 7.97 280 118.0 281 8.90 282 6.35 283 13.9 284 7.86 285 78.3 2897.05 290 14.2 291 17.5 292 462.5 293 279.0 294 1360.0 295 0.52 296 1.78298 0.87 299 3.06 300 0.89 305 0.996 307 2.22 308 1.99 309 0.36 310 10.7311 0.83 312 1.16 313 6.03 314 1.37 315 0.78 316 1.01 317 1.06 318 0.87319 3.44 320 1.70 321 0.65 322 0.51 323 0.82 324 2.51 325 1.64 326 0.74327 0.23 328 4.55 329 2.02 330 0.91 331 0.90 332 0.41 333 1.68 334 0.53335 0.40 336 0.50 337 1.40 338 0.82 339 0.75 340 0.12 341 0.30 342 135.0343 1.05 344 1.92 345 0.24 346 0.72 347 2.72 348 0.66 349 0.90 350 0.58351 0.81 352 1.55 353 0.42 354 0.92 355 2.13 356 0.57 358 0.10 360 0.25362 2.37 364 1.67 365 1.30 366 1.59 367 4.05 368 5.54 370 2.10 371 2.96372 1.13 373 3.48 374 20.9 375 3.93 376 0.85 377 0.82 378 0.56 379 0.17380 1.03 381 0.28 382 0.80 383 0.32 385 135.0 386 111.0 387 37.8 38830.5 389 106.0 390 69.7 391 51.5 392 121.0 393 6.68 394 198.0 395 130.0396 23.1 398 77.5 399 65.8 418 79.5 419 1.17 420 0.33 421 0.26 422 13.6423 0.34 424 0.23 425 1.01 426 2.19 427 3.23 428 2.48 429 2.53 430 2.64431 2.07 432 3.41 433 1.95 434 1.02 435 0.78 436 0.99 437 1.24 438 49.6439 34.2 440 22.7 441 70.5 442 27.4 443 1.19 444 1.18 445 1.78 446 1.98447 17.9 448 2.02 451 6.35 452 29.0 453 39.4 454 4.71 455 183.0 456462.0 457 377.0 458 35.9 459 128.0 460 42.7 461 1.32 462 1.54 463 1.44464 0.81 465 0.16 500 0.74 501 567.0 502 3920.0 503 563.0 504 39.3 5059770 506 493.6 507 23.9 508 383.0 509 0.36 510 165.0 511 35.7 512 1.02513 254.0 514 20.8 516 >10,000 517 >10,000 518 19.0 519 24.4 520 84.0521 >10,000 522 213.4 523 >10,000 524 >10,000 525 >10,000 526 >10,000527 >10,000 528 >10,000 529 >10,000 530 >10,000 531 >10,000 532 >10,000533 >10,000 534 >10,000 535 5720 536 4300 537 569. 538 >10,000539 >10,000 541 897 542 283 543 2640 544 204.0 546 3530 547 42.6 548132.0 549 1220 550 13.5 551 37.4 552 92.0 553 11.0 554 80.4 555 0.25 5561.27 564 0.22 565 0.38 566 0.77 567 1.41 568 1.36 569 0.83 570 0.24 5710.23 572 5600 573 896 576 0.46 578 164.0 579 0.83 581 9.00 582 40.00 6001.11 601 7.59 602 1.11 603 1.98 604 2.06 605 0.81 606 1.03 607 3.05 60810.00 609 10.00 610 10.00 611 0.37 612 1.85 613 0.83 614 1.69 616 17.95617 5.83 618 6.23 619 30.21 620 6.16 621 5.05 623 19.77 624 5.83 6255.50 626 158.30 627 4.66 628 20.21 629 19.58 633 18.87 634 6.49 635 4.80636 6.08 637 2.26 638 4.30 639 0.11 640 0.61 641 0.28 642 0.43 643 0.47644 0.42 647 0.44 648 320.4 649 35.44 650 21.43 651 5.87 652 17.34 653177.1 654 1.10 655 26.55 656 8.17 657 2.18 658 0.32 659 0.75 660 19.2661 25.74 662 29.86 663 1.60 664 117.90 665 44.36 666 8.02 667 0.04 6683.25 669 1.40 670 10.00 671 10.00 672 10.00 673 10.00 674 10.00 67525.49 677 56.99 678 6.73 679 0.53 680 115.7 681 7.54 682 10.00 683 10.00684 10.00 685 10.00 686 10.00 687 18.68 688 76.33 689 25.05 690 23.51691 0.35 692 0.48 693 0.37 694 0.46 695 0.19 696 0.29 697 0.34 698 0.26699 0.55 700 0.94 701 0.52 702 0.84 703 0.72 704 20.11 705 11.78 70615.04 707 13.72 708 9.42 709 17.45 710 23.32 711 17.87 712 27.59 7134.87 714 27.61 715 5.16 716 5.76 717 5.25 718 4.41 719 4.34 720 5.21 72117.62 722 0.57 723 0.88 726 10.58 727 75.12 728 104.9 729 476.6 733 3.77734 72.8

EXAMPLE 68 Filtration Binding Assay: ORL-1, Mu, Kappa and Delta OpioidReceptors

The assay used to measure the binding of representative test compoundsto the ORL-1, delta, kappa and mu opioid receptors was run similarly,with appropriate selection and substitution of cell membrane andradiolabeled ligand. The following cell membranes and ligands were usedfor the determination of binding to the respective opioid receptors.

ORL-1 (Nociceptin) 1 μg/well of 3C4 cell line membrane and 0.5 nM finalconcentration of ¹²⁵I nociceptin Delta (δ) opioid: 1 μg/well of 2D4 cellline membrane and a final concentration of 2.44 nM DPDPE-³H ligand. Mu(μ) opioid: 5 μg/well of 1D4 cell line membrane and a finalconcentration 0.8993 nM DAMGO-³H ligand. Kappa (κ) opioid: 7 μg/well of2C2 cell line membrane and a final concentration of 2.76 nM U-69,593-³Hligand.

Both membrane and ligand were diluted such that a 25 μl additiondelivered the necessary amount per well, as noted above. Both membraneand ligand were diluted in 1× ORL-1 buffer. The ORL-1 buffer wascomposed of 50 mM Tris-HCl, pH=7.4, 5 mM MgCl₂ and 1 mM EGTA. Each testcompound was diluted to a concentration in the range of from 100 μM to10 μM (half-log curve) with 100% DMSO. To each well of a 96 well platewas added 25 μL cell membrane (as listed above), 1 μL of the dilutedtest compound, and 25 μL labeled ligand (as listed above) for the mu,delta, kappa or ORL-1 opioid receptor, as desired.

The plate was incubated on a rotating shaker for 2 hours at roomtemperature. The plate was filtered over GF/C Filterplates, prewetted in0.03% polyethyleneimine, in Filtermate 196 apparatus (Packard). Theplate was then washed 6 times with ORL-1 buffer in the filtrationapparatus and dried in vacuum oven for 1 hour at a temperature of 50° C.

To each well was then added 25 μL Microscint 20 (Packard) (to solubilizebound radioactivity) and each well counted in a Packard TopCount for 1minute/well using counting parameters optimized for the particularradioligand/opioid receptor being tested. Percent radioactive ligandbound in each reaction was calculated relative to a control using DMSOfor maximum binding (no inhibition). Curves were fitted and K_(i)'sdetermined using Graphpad Prizm software (v3.0). The K_(i)s werecalculated using the following formula by Graphpad Prizm software, whereKi=(IC₅₀)/(1+[radioligand]/K_(d))

For the ORL-1, the K_(d) is 0.5nM, for Mu it is 0.8993 nM, for kappa itis 2.76 nM and for delta it is 2.44 nM. Note that the [radioligand](concentration of radioligand) was equivalent to the K_(d).

Representative compounds of the present invention were tested forbinding to the mu, kappa and delta opioid receptors using the procedure,cell membranes and ligands as described above, with results as listed inTable 13. The values listed below correspond to IC₅₀ measurements,unless followed with the notation “Ki” which denotes that for the listedvalue is a Ki measurement. (Note that for the compounds which weretested more than once, the value listed in Table 13 is the calculatedmean.)

TABLE 13 ID# Delta IC₅₀ (μM) Kappa IC₅₀ (μM) Mu IC₅₀ (μM) 1 >10 0.130.62 2 >10 0.19 1.20 3 9.16 0.44 4.05 4 >10 0.11 0.16 5 >10 0.12 0.786 >10 0.23 0.42 7 7.11 0.13 1.38 8 0.05 0.83 9 1.40 0.94 10 0.08 0.85 110.29 0.82 12 0.20 0.52 13 0.12 0.62 14 0.40 1.20 15 0.33 0.85 16 0.551.12 17 >10 0.25 0.65 18 >10 0.28 0.45 19 0.09 0.59 20 >10 0.44 1.2821 >10 0.32 0.80 22 0.30 0.60 23 0.49 9.20 24 >10 0.75 1.25 25 0.45 1.1026 0.29 0.79 27 0.03 0.40 28 >10 0.18 0.41 29 0.41 5.41 30 >10 0.71 2.7331 0.28 2.93 32 >10 0.27 0.45 33 1.16 >10 34 0.27 0.68 35 >10 0.66 0.8236 1.76 0.23 1.76 38 >10 0.20 0.99 39 >10 3.25 8.83 40 >10 0.40 1.2241 >10 0.25 2.10 42 0.26 0.54 43 0.32 0.54 44 0.16 1.13 45 1.18 0.100.51 46 9.87 0.19 1.32 47 >10 0.09 0.21 48 >10 0.17 0.54 49 0.08 50 1.0451 0.18 52 4.41 0.05 0.29 53 4.74 0.03 0.07 54 >10 0.11 0.35 55 3.900.37 0.60 56 1.25 0.50 0.08 57 0.07 58 1.12 59 0.10 60 0.35 61 0.64 0.080.32 62 0.90 0.10 0.06 63 8.78 0.23 3.43 64 7.34 0.24 1.19 65 0.51 0.5866 5.93 0.13 0.55 67 >10 0.04 0.71 68 >10 0.02 0.26 69 >10 0.04 0.51 700.63 71 0.57 72 0.79 1.84 73 >10 0.25 0.68 74 8.02 0.09 0.89 75 >10 0.300.98 76 >10 0.02 0.51 78 0.82 79 1.04 3.11 100 >10 0.28 0.23 101 3.930.78 0.076 102 0.18 103 0.02 104 0.52 0.08 0.02 105 2.26 106 0.016 1070.003 108 0.54 115 0.012 116 0.022 117 0.036 124 0.023 127 0.029 1290.029 130 0.061 131 0.051 132 0.043 133 0.087 137 0.100 138 0.066 1390.103 140 0.074 142 0.104 143 0.048 144 0.049 145 0.104 146 0.038 1470.044 148 0.037 149 0.057 152 0.044 153 0.057 155 0.050 156 0.016 1580.066 159 0.068 160 0.021 161 0.049 164 0.082 165 0.011 166 0.022 1670.053 168 0.010 169 0.057 171 0.037 173 0.038 174 0.022 175 0.030 1760.055 177 0.047 178 0.018 179 0.020 180 0.045 181 0.034 183 0.047 1922.51 0.01 203 3.08 0.02 0.04 228 0.070 229 0.060 230 0.152 250 >10 0.381.20 251 >10 0.45 1.58 252 >10 1.34 3.70 253 2.16 0.40 0.76 254 >10 0.802.83 255 >10 0.62 2.49 256 >10 1.18 5.45 257 >10 0.38 0.88 259 0.50261 >10 0.27 1.56 262 0.85 263 0.59 267 0.77 268 0.95 269 2.49 270 0.41271 >10 0.07 0.37 275 5.01 0.09 0.45 276 >10 0.70 0.86 280 1.08 2.52 2810.96 0.58 282 0.77 0.324 283 1.15 3.24 284 0.42 3.20 285 2.69 4.78 2890.19 1.39 290 0.93 291 0.57 4.56 298 6.06 0.05 0.38 299 >10 1.98 0.43300 4.84 0.13 0.51 305 8.27 0.171 0.592 307 0.21 0.75 308 0.05 0.20 3090.09 0.04 310 1.63 1.09 311 1.70 0.28 0.27 312 0.33 0.32 313 0.50 0.33314 0.16 0.13 315 0.28 0.30 316 0.19 0.49 317 0.22 0.92 318 0.08 0.23319 0.58 0.32 320 0.12 0.34 321 0.15 0.16 322 0.22 0.13 323 0.10 0.72324 0.23 0.11 325 0.21 0.73 326 0.01 0.25 327 >10 0.11 0.13 328 0.301.03 330 >10 0.48 0.19 331 0.12 0.46 332 0.02 0.08 333 0.39 0.24 3340.03 0.06 335 0.07 0.13 336 0.04 0.06 337 0.25 0.55 338 0.14 0.74339 >10 0.18 0.21 340 7.34 0.495 1.29 341 >10 0.29 0.81 342 >10 0.290.35 343 2.70 0.42 0.55 344 4.81 0.23 0.55 345 9.27 0.668 0.37 346 1.100.14 0.17 347 9.13 0.62 5.4 348 >10 0.93 5.42 349 >10 0.38 1.4 350 3.160.078 0.25 351 8.00 0.081 0.38 352 >10 0.27 0.94 353 8.89 0.24 0.47354 >10 0.15 0.30 355 4.15 0.16 0.18 356 >10 0.08 0.63 358 2.46 0.130.17 360 2.51 0.03 0.15 362 0.82 0.20 364 0.18 0.21 365 0.79 1.75 3660.34 0.26 367 0.36 1.86 368 0.43 1.08 370 0.29 0.35 371 0.73 0.57 3720.26 0.70 373 1.24 0.37 374 0.73 1.96 376 0.14 0.07 377 2.61 0.093 0.16378 0.20 0.64 379 0.14 0.16 380 0.23 0.07 381 0.10 0.22 382 0.21 0.15383 0.06 0.54 386 3.69 >10 388 0.23 >10 389 9.84 7.06 390 1.22 1.79 3912.18 >10 392 1.39 >10 393 1.04 >10 395 >10 1.10 396 0.81 >10 398 >100.25 >10 399 0.75 >10 418 >10 >10 >10 419 0.16 0.13 420 >10 0.42 0.41421 0.13 0.04 422 >10 >10 423 >1 0.59 0.31 424 0.28 0.60 0.28 425 0.820.29 426 >10 1.06 2.74 427 1.45 2.37 428 0.75 0.90 429 0.67 0.80 430 >100.89 2.47 431 0.58 1.74 432 0.37 1.00 433 0.42 1.26 434 0.88 0.24 4350.60 0.22 436 0.83 0.25 437 1.40 0.36 438 >10 >10 439 >10 >10440 >10 >10 441 >10 >10 442 >10 >10 443 1.75 0.17 444 1.71 0.25 445 >100.10 0.06 446 4.12 0.13 0.45 447 0.48 0.48 448 0.17 1.14 451 0.77 0.32452 1.52 0.57 453 0.39 1.70 454 0.12 0.51 455 0.38 5.16 456 >10 >10 4579.43 >10 458 1.45 >10 459 3.21 >10 460 0.83 0.90 461 >10 0.25 1.03 4625.62 0.15 0.12 463 1.77 0.17 464 0.34 2.38 465 0.10 0.38 505 >10 >10 >10506 0.67 0.529 507 >10 0.277 1.29 508 0.874 0.156 509 0.50 0.11 0.02 5105.77 0.24 0.69 511 3.91 0.42 0.14 512 0.82 0.98 0.086 513 0.46 0.05 5140.21 0.26 516 0.77 >10 517 0.45 >10 541 9.28 2.14 0.48 542 >10 0.53 0.16543 >10 0.71 2.09 544 >10 0.379 0.582 546 >10 2.13 1.29 547 >10 >10 >10548 >10 0.07 0.54 549 >10 4.37 >10 550 2.61 0.09 0.16 551 1.51 552 >101.22 0.066 553 >10 0.75 3.4 554 10.0 9.47 >10 555 0.1 0.56 0.10 556 >100.438 0.382 564 0.49 0.04 565 0.41 0.03 566 0.98 0.27 567 1.00 0.17 5680.72 0.11 569 0.29 0.14 570 0.79 0.05 571 0.05 0.20 0.04 572 3.87 9.85573 2.09 7.22 576 1.4 0.185 0.03 578 >10 2.86 579 2.75 0.17 600 0.490.04 601 1.77 0.77 602 0.88 0.07 603 1.32 0.08 604 0.79 0.08 605 0.332.38 606 0.58 0.09 607 10.0 10.0 608 10.0 10.0 609 10.0 10.0 610 9.0210.0 611 0.18 0.05 612 0.44 0.28 613 0.51 0.27 614 1.58 0.56 616 >5 Ki0.09 Ki 0.20 Ki 617 >5 Ki 0.02 Ki 0.09 Ki 618 >5 Ki 0.04 Ki 0.08 Ki619 >5 Ki 0.17 Ki 0.14 Ki 620 >5 Ki 0.19 Ki 0.28 Ki 621 >5 Ki 0.02 Ki0.04 Ki 623 >5 Ki 0.03 Ki 0.14 Ki 624 >5 Ki 0.006 Ki  0.07 Ki 625 0.35Ki   0.003 Ki  0.01 Ki 626 1.45 Ki   0.05 Ki 0.05 Ki 627 >5 Ki 0.01 Ki0.06 Ki 628 1.43 Ki   0.008 Ki  0.03 Ki 629 >5 Ki 0.01 Ki 0.07 Ki 633 >5Ki 0.04 Ki 0.44 Ki 634 >5 Ki 0.03 Ki 0.12 Ki 635 >5 Ki 0.03 Ki 0.13 Ki636 3.40 Ki   0.01 Ki 0.23 Ki 637 >5 Ki 0.08 Ki 0.10 Ki 638 >5 Ki 0.07Ki 0.40 Ki 639 1.60 Ki   0.03 Ki 0.01 Ki 640 >5 Ki 0.21 Ki 0.12 Ki 6411.58 Ki   0.02 Ki 0.01 Ki 642 3.06 Ki   0.08 Ki 0.02 Ki 643 4.42 Ki  0.04 Ki 0.01 Ki 644 2.28 Ki   0.03 Ki 0.03 Ki 647 >5 Ki 0.02 Ki 0.05 Ki648 >5 Ki 2.87 Ki 5.00 Ki 649 >5 Ki 0.68 Ki 0.89 Ki 650 >5 Ki 0.46 Ki0.74 Ki 651 >5 Ki 0.31 Ki 0.67 Ki 652 >5 Ki 0.75 Ki 1.06 Ki 653 >5 Ki1.58 Ki 5.00 Ki 654 >5 Ki 0.06 Ki 0.13 Ki 655 >5 Ki 0.43 Ki 2.19 Ki656 >5 Ki 0.42 Ki 1.52 Ki 657 >5 Ki 0.04 Ki 0.09 Ki 658 >5 Ki 0.13 Ki0.17 Ki 659 >5 Ki 0.42 Ki 0.13 Ki 660 0.87 Ki 661 0.80 Ki 662 1.60 Ki663 >5 Ki 0.018 Ki  0.071 Ki  664 >5 Ki 0.72 Ki 0.26 Ki 665 >5 Ki 0.29Ki 2.71 Ki 666 >5 Ki 0.14 Ki 2.59 Ki 667 4.14 Ki   0.45 Ki 0.77 Ki 6681.25 0.19 669 1.36 0.13 670 10.00 10.00 671 10.00 10.00 672 10.00 10.00673 10.00 10.00 674 10.00 10.00 675 3.10 Ki   0.01 Ki 0.04 Ki 677 0.53Ki   0.10 Ki 0.08 Ki 678 5.0 Ki  0.04 Ki 0.14 Ki 679 1.52 Ki   0.03 Ki0.05 Ki 680 >5 Ki 0.66 Ki 3.02 Ki 681 >5 Ki 0.58 Ki 0.71 Ki 682 10.0010.00 683 10.00 10.00 684 5.90 10.00 685 10.00 10.00 686 2.52 10.00 6870.51 Ki   0.01 Ki 0.01 Ki 688 >5 Ki 0.16 Ki 0.11 Ki 689 1.46 Ki   0.005Ki  0.01 Ki 690 1.07 Ki   0.004 Ki  0.03 Ki 691 0.25 0.03 692 3.36 Ki  0.06 Ki 0.02 Ki 693 0.03 0.17 694 0.01 0.85 695 0.16 0.18 696 0.05 0.04697 0.16 0.20 698 0.19 0.17 699 0.07 0.19 700 0.03 0.92 701 0.05 0.20702 0.41 0.30 703 0.45 0.11 704 >5 Ki 0.34 Ki 1.33 Ki 705 >5 Ki 0.71 Ki1.50 Ki 706 0.48 Ki 707 0.55 Ki 708 0.49 Ki 709 0.89 Ki 710 >5 Ki 0.36Ki 1.09 Ki 711 0.82 Ki 712 1.95 Ki 713 0.23 Ki 714 >5 Ki 0.59 Ki 715 >5Ki 0.15 Ki 0.56 Ki 716 >5 Ki 0.47 Ki 1.31 Ki 717 >5 Ki 0.33 Ki 1.32 Ki718 >5 Ki 0.03 Ki 0.48 Ki 719 >5 Ki 0.17 Ki 0.64 Ki 720 >5 Ki 0.16 Ki0.57 Ki 721 >5 Ki 0.17 Ki 0.59 Ki 722 0.44 0.48 723 0.83 0.08 726 0.53Ki   0.005 Ki  0.04 Ki 727 >5 Ki 0.21 Ki 0.12 Ki 728 >5 Ki 0.14 Ki 0.08Ki 729 0.35 Ki   0.01 Ki 0.003 Ki  733 >5 Ki 0.07 Ki 0.08 Ki 734 >5 Ki1.93 Ki   >5 Ki

EXAMPLE 69 In Vitro Assay—Filtration Binding Assay, Dopamine

The assay was used to measure the binding of representative compounds toD2 receptor, with appropriate selection and substitution of cellmembrane and radiolabeled ligand. The following cell membranes andligands were used for the determination of binding to the respective D2receptor.

-   -   Dopamine: 0.4 μg/well of membrane from cos-7 cell which has been        transfected with cloned human Dopamine, Spiperone-I125 ligand at        150 μM final

Both membrane and ligand were diluted such that a 25 μl additiondelivered the necessary amount per well, as noted above. Both membraneand ligand were diluted in TNE buffer. The TNE buffer was a mixture of50 mM Tris-HCl pH=7.4, 5 mM EDTA and 50 mM NaCl. Each test compound wasdiluted to a concentration from 10 μM to 1 μM with 100% DMSO. To eachwell of a 96 well plate was added 140 μL of TNE buffer, 10 μL of thediluted test compound in DMSO, 25 μL of spiperone and 25 μL of membrane.

The plate was incubated on a rotating shaker for 1 hour at roomtemperature. The plate was filtered over GF/C Filterplates, prewetted in0.03% polyethleneimine, in Filtermate 196 apparatus (Packard). The platewas then washed 6 times with ORL-1 buffer in the filtration apparatusand dried in vacuum oven for 1 hour at a temperature of 50° C.

To each well was then added 25 μL Microscint 20 (Packard) (to solubilizebound radioactivity) and each well counted in a Packard TopCount for 1minute/well using counting parameters optimized for the particularradioligand/opioid receptor being tested. Percent radioactive ligandbound in each reaction was calculated relative to a control using DMSOfor maximum binding (no inhibition). Curves were fitted and Kidetermined using Graphpad Prizm software (v3.0).

Representative compounds of the present invention were tested accordingto the procedure outlined above with results as listed in Table 14.

TABLE 14 ID # IC₅₀ (nM) 422 2208 424 278.2 426 >10,000 430 >10,000 4333520 439 2334 440 1517 442 3229 327 387.5

EXAMPLE 70 Elevated Plus Maze (EPM) and Spontaneous Locomotor Activity(SMA) (Pellow, S., Chopin, P., File. S. E. and Briley, M., J NeurosciMethods, (1985) 14, 149-167)

The procedure used in the EPM was based on the natural aversion ofrodents to explore brightly illuminated open and high places, as well astheir innate tendency for thigmotaxis. When rats are placed on theelevated-plus maze, they have a normal tendency to remain in theenclosed arms of the maze and avoid venturing into the open arms.Animals treated with typical or atypical anxiolytics show an increase inthe percentage of time spent (% Time) and/or the percentage of entriesmade (% Entries) into the open arms.

The spontaneous locomotor activity test (SMA) was an automated procedurefor measuring the effect of a test compound on spontaneous motoractivity in an open-field. A drug-induced decrease in spontaneoushorizontal or vertical motor activity is regarded as an indication ofsedation.

Animals

Male Long-Evans Hooded rats weighing 180 to 200 grams were purchasedfrom Charles River Inc (Portage Mich.). The rats were housed in groupsof four at an ambient temperature of 21 to 23° C. in a room with anautomated 12/12 hour light/dark cycle, and access to water and acommercial rodent food ad libitum.

EPM Test Apparatus

Each black plastic maze had two open arms and two arms with 40 cm highwalls (enclosed arms) of equal 50 cm length extending from the center atright angles, such that arms of similar type are opposite each other.Each plus-maze was elevated approximately 60 cm above the floor.Infrared photo-beams that cross the entrance of each arm and the centerof the maze detected the exploratory activity of an animal in the maze.Rats were divided into groups (N=8 to 12) and test compound or vehiclewas administered either orally (p.o.) by gavage in a dose volumeequivalent to 5 mL/kg or intraperitoneally (i.p.) in a dose volume of 1mL/kg. One hour after dosing (for p.o. administration) or 30 minutesafter dosing (for i.p. administration), rats were placed on an open armof the plus-maze facing the center. The 10 minute test was initiatedwhen the rat enters the center of the apparatus. Data collection wasautomated.

SMA Test Apparatus

The test apparatus consisted of a plastic cubicle (42.0 cm in length;42.0 cm in width and 30.5 cm height) that was placed in the center of amain frame. Photocell sensors (16 beams from front to back and 16 beamsfrom side to side) were built into the sides of the frame for monitoringhorizontal movement. The photocells were located at right angles to eachother, projecting horizontal infrared beams of light 2.5 cm apart and 3cm above the floor to measure horizontal activity, and 2.5 cm apart and14 cm above the floor to measure vertical activity. Rats were dividedinto groups (N=8 to 12). Test compound or vehicle was administeredeither orally (p.o.) by gavage in a dose volume equivalent to 5 mL/kg orintraperitoneally (i.p.) in a dose volume of 1 mL/kg. At 50 minutesafter p.o. administration or at 20 minutes after i.p. administration,each rat was placed into a separate plastic cubicle, and spontaneousexploratory activity was recorded for 10 minutes. Horizontal activityand vertical movements of the rats were recorded by counting the numberof times the beams of light were interrupted (horizontal and verticalcounts). Collection of the data and preliminary data analysis wasautomated.

Combined SMA/EPM Test Procedure

All animals were tested in the SMA 50 minutes after drug administration,for a 10 minute test session. Upon completion of the SMA test, the sameanimals were immediately placed on the EPM for a 10 minute test session.

Test Compounds

The test compound was dissolved in polyethylene glycol, molecular weight200 (PEG-200) for i.p. administration. Test compound was suspended in anaqueous vehicle (MC) comprised of 0.5% Methylcellulose for p.o.administration.

Derivation and Analysis of EPM Data

Anxiolytic activity of a test compound in the EPM was quantified usingtwo parameters. The percent of total time spent by a rat in one of thetwo open arms of the apparatus (% open arm time) was calculated as 100×(time on open arms)/(total time of test session)

The number of times a rat entered the open arms relative to the totalentries into all arms and the center area (% open arm entries) wascalculated as 100× (entries into open arms)/(entries into open andclosed arms, plus center)

A test compound was considered active in rats whose % open arm time or %open arm entries was significantly greater than in rats that receivedvehicle. Data was analyzed for statistical significance between drug andvehicle-treated groups via one tailed Mann-Whitney T-Test. If theprobability was less than 5% (p<0.05) that an increase in the % open armtime and/or % open arm entries in the drug-treated group compared to thevehicle-treated group was due to chance, then the dose of the testcompound was considered active.

The total number of entries into all arms and the center of the EPM wasrecorded as part of the automated data collection in this test. Thisinformation (total entries) served as a measure of spontaneous motoractivity on the EPM. Compounds with sedative activity reduced the totalnumber of entries in the EPM test. A test compound was considered tohave sedative activity in rats whose total entries were significantlyless than in rats that received vehicle. Data was analyzed forstatistical significance between drug and vehicle-treated groups via onetailed Mann-Whitney T-Test. If the probability was less than 5% (p<0.05)that a decrease in the total entries in the drug-treated group comparedto the vehicle-treated group was due to chance, then the dose of thetest compound was considered to be a dose at which the compound producessedation.

Derivation and Analysis of SMA Data

A test compound was considered sedative in rats whose horizontalactivity (HA) or vertical movements (VM, rearing) counts weresignificantly less than that in vehicle-treated rats. HA data wasanalyzed for statistical significance between drug and vehicle-treatedgroups that were administered either the vehicle or each dose of thetest compound by a one-way analysis of variance. Then Dunnett's multiplecomparison method was used to test for a reduction (p<0.05, 1-tailed) inthe average number of HA counts or VM counts in drug-treated groups,compared to a concurrently run vehicle-treated group. If the probabilitywas less than 5% (p<0.05) that a decrease in HA and/or VM in thedrug-treated group compared to a concurrently run vehicle-treated groupwas due to chance, then the dose of the test compound was considered tohave sedative activity. Mann-Whitney T-Test was used in cases where thedistribution of the data was non-gaussian.

Representative compounds of the present invention were tested accordingto the EPM and SMA procedures described above, with results as listed inTable 15-19, below. Statistical significance (P<0.05) was determinedusing a Mann-Whitney U Test (one-tailed); NS indicates results were notstatistically significant.

TABLE 15 EPM and SMA Assay Results Acute (30 min) IntraperitonealAdministration Compound #64(*) % Open % Open Total Horizontal VerticalDosage mg/kg, i.p. Arm Time Arm Entries Entries Activity Movement (#Animals) Statistics (EPM) (EPM) (EPM) (SMA) (SMA) Vehicle Mean 8.92 5.5094.8 3210 50.0 (PEG-200) S.E.M. ±1.65 ±0.86 ±4.11 ±158 ±2.82 (40) %Change 0.0% 0.0% 0.0% 0.0% 0.0% 0.03 Mg/Kg Mean 9.21 5.92 95.7 3259 49.8(28) S.E.M. ±2.14 ±1.17 ±2.73 ±169 ±2.37 % Change 3.2% 7.6% 0.95%  1.5%−0.4% P-value NS NS NS NS NS  0.1 Mg/Kg Mean 15.3 10.6 95.4 3845 55.7(32) S.E.M. ±1.97 ±1.17 ±3.91 ±200 ±2.72 % Change 71.5% 92.7% 0.63% 19.8% 11.4% P-value 0.0053 0.0004 NS 0.0091 NS  0.3 Mg/Kg Mean 13.7 7.8699.7 3561 58.0 (32) S.E.M. ±1.96 ±0.87 ±3.60 ±181 ±2.69 % Change 53.6%42.9% 5.2% 10.9% 16.0% P-value 0.0159 0.0146 NS NS 0.0270   1 Mg/Kg Mean14.0 7.78 94.8 3611 53.8 (32) S.E.M. ±2.11 ±0.89 ±3.73 ±184 ±1.83 %Change 57.0% 41.4% 0.0% 12.5% 7.6% P-value 0.0155 0.0099 NS NS NS   3Mg/Kg Mean 11.2 7.38 90.8 3449 51.1 (28) S.E.M. ±1.86 ±1.00 ±3.90 ±172±2.14 % Change 25.6% 34.2% −4.2%   7.4% 2.2% P-value NS NS NS NS NS   10Mg/Kg Mean 11.8 7.36 86.8 2803 46.9  (8) S.E.M. ±4.03 ±1.85 ±6.91 ±165±3.72 % Change 32.3% 38.8% −8.4% −12.7%    −6.2% P-value NS NS NS NS NS(*)Compound #64 was also tested in the SMA and EPM assays, using oraladministration, but found to be inactive.

TABLE 16 EPM and SMA Assay Results Acute (1 hr) Oral Administration -Mixture 3 Parts Compound #422(*): 1 Part Compound #438 % Open % OpenDosage Arm Arm Total Horizontal Vertical mg/kg, p.o. Time EntriesEntries Activity Movement (# Animals) Statistics (EPM) (EPM) (EPM) (SMA)(SMA) Vehicle Mean 9.61 6.59 102.0 3085 50.7 (0.5% S.E.M. ±1.04 ±0.59±3.02 ±129 ±1.27 Methylcellulose) % Change 0.0% 0.0% 0.0% 0.0% 0.0% (80)0.03 Mg/Kg Mean 7.80 5.53 88.3 3307 53.6 (16) S.E.M. ±1.82 ±1.00 ±5.25±240 ±2.41 % Change −18.8% −16.1% 13.4% 7.2% 5.7% P-value NS NS 0.0235NS NS  0.1 Mg/Kg Mean 11.5 7.73 101 3467 59.4 (32) S.E.M. ±1.97 ±1.04±3.56 ±165 ±2.50 % Change 19.7% 17.3% −1.0% 12.4% 17.2% P-value NS NS NS0.0077 0.0011  0.3 Mg/Kg Mean 12.1 7.85 98.7 3397 53.7 (56) S.E.M. ±1.38±0.64 ±2.26 ±150 ±1.68 % Change 25.9% 19.1% −3.2% 10.1% 5.9% P-value NS0.0444 NS 0.0227 0.0408   1 Mg/Kg Mean 14.0 9.55 99.7 3645 55.7 (48)S.E.M. ±1.68 ±0.75 ±3.34 ±164 ±1.83 % Change 45.7% 44.9% −2.3% 18.2%9.9% P-value 0.0082 0.0009 NS 0.0015 0.0180   3 Mg/Kg Mean 14.0 8.88102.0 3621 55.0 (48) S.E.M. ±1.44 ±0.70 ±2.23 ±188 ±1.81 % Change 45.7%34.7% 0.0% 17.4% 8.5% P-value 0.0032 0.0043 NS 0.0051 0.0338   10 Mg/KgMean 17.0 10.3 97.6 3207 51.5 (56) S.E.M. ±1.51 ±0.77 ±3.06 ±124 ±1.51 %Change 76.9% 56.3% −4.3% 4.0% 1.6% P-value P < 0.0001 P < 0.0001 NS NSNS   30 Mg/Kg Mean 10.6 8.90 80.7 2741 46.3 (24) S.E.M. ±1.55 ±1.16±4.20 ±171 ±2.39 % Change 10.3% 35.1% −20.9% −11.2% −8.7% P-value NS0.0197 P < 0.0001 NS 0.0091 (*)Compound #422 was also tested in the SMAand EPM assays, using oral administration, but was found to be inactive.

TABLE 17 EPM and SMA Assay Results Acute (1 hr) Oral AdministrationCompound #424(†) % Open % Open Dosage Arm Arm Total Horizontal Verticalmg/kg, p.o. Time Entries Entries Activity Movement (# Animals)Statistics (EPM) EPM (EPM) (SMA) (SMA) Vehicle Mean 5.76 5.48 96.7 288149.1 (0.5% Methylcellulose) S.E.M. ±1.50 ±1.21 ±4.65 ±208 ±3.28 (24) %Change 0.0% 0.0% 0.0% 0.0% 0.0% 0.3 Mg/Kg Mean 9.80 7.33 90.0 3033 54.6(24) S.E.M. ±2.09 ±1.09 ±4.90 ±232 ±3.11 % Change 70.1% 33.8% −6.9% 5.3%11.2% P-value 0.0206 NS NS NS NS 1 Mg/Kg Mean 9.76 7.49 91.5 2752 50.3(24) S.E.M. ±1.83 ±1.28 ±3.11 ±188 ±3.65 % Change 69.4% 36.7% −5.3%−4.5% 2.4% P-value NS NS NS NS NS 3 Mg/Kg Mean 10.1 7.92 96.3 3300 56.8(24) S.E.M. ±1.83 ±1.15 ±3.43 ±145 ±2.35 % Change 75.3% 44.5% −0.4%14.5% 15.7% P-value 0.0426 0.0398 NS 0.0239 NS 10 Mg/Kg Mean 7.54 7.49102.6 2588 44.2 (24) S.E.M. ±1.75 ±1.32 ±4.63 ±215 ±3.32 % Change 30.9%36.7% 6.1% −10.2% −10.1% P-value NS NS NS NS NS (†)Compound #424 wasalso tested in the SMA and EPM assays, using intraperotinealadministration, with the following results.

In the rat EPM, at doses of 0.1 mg/kg, 0.3 mg/kg and 3.0 mg/kg, Compound#424 produced significant increases in percent open arm time (P<0.04)with peak activity occurring at doses 0.1 mg/kg and 3 mg/kg (97.5%increase as compared to vehicle). At doses of 0.1 mg/kg, 0.3 mg/kg, 3.0mg/kg, and 10.0 mg/kg Compound #424 also produced significant increasesin percent open arm entries (P<0.03) with peak activity occurring at 3.0mg/kg and 10.0 mg/kg doses (205% and 237% increase as compared to fromvehicle, respectively). Compound #424 significantly reduced the totalnumber of entries into various zones of the maze at doses 1.0 mg/kg, 3.0mg/kg and 10.0 mg/kg (18.6%, 60.3%, and 76.7% reductions, respectively).

In the rat SMA, at doses of 3.0 mg/kg and 10.0 mg/kg, Compound #424produced significant reductions (55% and 83.7% reductions, respectively)in horizontal activity (P<0.001; Dunnett's multiple comparison test). Atdoses of 1.0 mg/kg, 3.0 mg/kg and 10.0 mg/kg (17.8%, 73.4%, 93.9%reductions, respectively) Compound #424 produced significant reductions(P<0.05; Dunnett's multiple comparison test) in the number of verticalmovements (rearing behavior).

TABLE 18 EPM and SMA Assay Results Acute (1 hr) Oral Administration ofCompound #438 % Open % Open Dosage Arm Arm Total Horizontal Verticalmg/kg, p.o. Time Entries Entries Activity Movement (# Aminals)Statistics (EPM) (EPM) (EPM) (SMA) (SMA) Vehicle Mean 8.21 5.78 101.03244 48.7 0.5% Methylcellulose S.E.M. ±1.18 ±0.532 ±3.81 ±168 ±1.85 (40)% Change 0.0% 0.0% 0.0% 0.0% 0.0% 0.03 Mg/Kg Mean 6.67 5.14 102.0 356554.8 (24) S.E.M. ±1.59 ±0.984 ±3.67 ±216 ±2.75 % Change −18.8% −11.1%1.0% 9.9% 12.5% P-value NS NS NS NS NS 0.1 Mg/Kg Mean 12.1 7.77 103 343553.1 (24) S.E.M. ±1.92 ±0.913 ±3.81 ±160 ±2.25 % Change 47.4% 34.4% 2.0%5.9% 9.0% P-value 0.0434 0.0352 NS NS NS 0.3 Mg/Kg Mean 13.8 8.95 99.83450 51.7 (24) S.E.M. ±1.56 ±0.891 ±3.64 ±155 ±2.36 % Change 68.1% 54.8%−1.2% 6.4% 6.2% P-value 0.0038 0.0010 NS NS NS 1 Mg/Kg Mean 14.8 9.95103.0 3772 56.6 (24) S.E.M. ±2.13 ±1.23 ±4.08 ±170 ±2.32 % Change 80.3%72.1% 2.0% 16.3% 16.2% P-value 0.0053 0.0025 NS NS NS 3 Mg/Kg Mean 12.48.34 101.0 3502 55.3 (24) S.E.M. ±1.73 ±1.02 ±4.75 ±223 ±2.17 % Change51.0% 44.3% 0.0% 8.0% 13.6% P-value 0.0170 0.0336 NS NS NS 10 Mg/Kg Mean8.14 6.4 94.5 3115 54.5 (24) S.E.M. ±1.30 ±0.856 ±3.41 ±168 ±1.73 %Change 0.9% 11.1% −6.4% −4.0% 11.9% P-value 0.3644 NS NS NS NS 30 Mg/KgMean 3.21 6.65 86.3 2730 45.3 (7/8) S.E.M. ±1.76 ±2.28 ±6.40 ±185 ±3.34% Change −60.9% 15.1% −14.6% −15.8% −7.0% P-value 0.0486 NS NS NS NS

TABLE 19 EPM and SMA Assay Results Sub-Chroinc (8-day/once a day) OralAdministration Compound #438 % Open % Open Dosage Arm Arm TotalHorizontal Vertical mg/kg, p.o. Time Entries Entries Activity Movement #Aminals Statistics (EPM) (EPM) (EPM) (SMA) (SMA) Vehicle Mean 7.96 6.53101.0 3451 54.6 (0.5% methylcellulose) S.E.M. ±1.87 ±1.05 ±4.72 ±196±3.35 (16) % Change 0.0% 0.0% 0.0% 0.0% 0.0% 0.1 Mg/Kg Mean 17.2 9.17102 3813 62.9 (16) S.E.M. ±1.84 ±0.931 ±4.82 ±170 ±1.75 % Change 116.1%40.4% 1.0% 10.5% 15.2% P-value 0.0012 0.0338 NS NS NS 0.3 Mg/Kg Mean21.8 11.8 99.1 4390 61.1 (16) S.E.M. ±1.8 ±0.891 ±5.56 ±253 ±3.61 %Change 173.9% 80.7% −1.9% 27.2% 11.9% P-value P < 0.0001 0.0007 NS P <0.05 NS   1 Mg/Kg Mean 15.1 9.57 99.6 3979 59.5 (16) S.E.M. ±1.96 ±1.12±3.42 ±151 ±2.53 % Change 89.7% 46.6% −1.4% 15.3% 9.0% P-value 0.00640.0007 NS NS NS   3 Mg/Kg Mean 16.9 9.0 106.0 4253 59.9 (16) S.E.M. ±2.9±1.21 ±4.42 ±306 ±3.47 % Change 112.3% 37.8% 5.0% 23.2% 9.7% P-value0.0047 0.0367 NS P < 0.05 NS

EXAMPLE 71 In Vivo Study—Vogel Rat Conflict Assay (Vogel, J. R., et al.,Psychopharmacology, (1971), 21, 1)

This behavioral assay assesses the anxiolytic activity of a testcompound by determining the ability of rats to release (disinhibit)behavior that has been suppressed by punishment.

Method

Male adult rats were deprived of water for 48 hours and were deprived offood for 24 hours prior to testing. After the first 24 hours of waterdeprivation, the rats were placed in the conflict chamber for a trainingperiod; during which time the rats were allowed 200 unpunished licksfrom a bottle containing tap water. The experiment was run the followingday. The rats were dosed with the test compound orally by gavage orintraperitoneally (i.p.). At the expected time of peak activity (30minutes for i.p administration and 60 min for oral administration), therats were placed in the conflict chamber and were allowed access to tapwater. If they failed to drink, the experiment was terminated in 5 min,and the animals were evaluated for signs of CNS depression. The firstlick initiated a 3min test session. Subsequently, every 20^(th) lick waspunished with an 0.2 sec, 0.6 milliampere (RMS) shock delivered via thestainless steel drinking tube. Vehicle treated control animals weregenerally willing to accept a median of 3 to 8 shocks per test session.Animals treated with an active anxiolytic drug tolerated significantlymore shocks than control animals. The Wilcoxon rank-sum test(Mann-Whitney U-test) was used to test for an increase (p<0.05, 1tailed) in the median number of shocks in the drug treated groupcompared with a concurrently run control treated group. The assay wasconsidered to be valid if the effects of a known anxiolytic (a positivecontrol) were detected within the same experiment. A test compound wasconsidered active if there was a significant difference in the mediannumber of shocks tolerated between the drug treated and the controlgroup.

Compound #64 and a mixture of three parts Compound #422 to one partCompound 438 (denoted as “CMPD mix” in the table below) were testedaccording to the procedure described above, with results as listed inTable 20, below. No./Group indicates the number of animals tested forthe listed dosage. % increase in mean no of shock is as compared withvehicle. Statistically significant results were those with aMann-Whitney U Test (one tailed) p value of <0.05.

TABLE 20 % Increase No/ Mean Group No. of Shocks P Value Dose (mg/kg,i.p.) PEG-200 (Vehicle) 0 25 0 — Compound #64 0.3 8 −10%  0.3294Compound #64 1 24 25% 0.3480 Compound #64 3 24 96% 0.0692 Compound #6410 22 150%  0.0002 Compound #64 30 8 −26%  0.5000 Dose (mg/kg, p.o.)0.5% Methylcellulose 0 17 0 — (Vehicle) CMPD mix 0.3 8  8% 0.3304 CMPDmix 1 8 39% 0.4418 CMPD mix 3 8 47% 0.0425 CMPD mix 10 18 54% 0.1634CMPD mix 30 12 47% 0.0327

EXAMPLE 72 Stress Induced Hyperthermia in Vivo Assay

Procedure

Male Long-Evans Hooded rats weighing 180 to 200 grams at the time ofpurchase were obtained from Charles River Laboratories (Raleigh, N.C.).Upon arrival, the animals were group housed four per cage in quarantinefor 5 days in wire-mesh cages at an ambient temperature of 21 to 23° C.with an automated 12/12 hour light/dark cycle and ad libitum access towater and a commercial rodent chow. The rats were then transferred to ageneral housing room for a one-week acclimation with housing andenvironmental conditions, and 12/12 hour light/dark cycle conditions.Animals were fasted overnight (18 hours) prior to experiment.

On the day of experiment, group-housed (4/group) Long-Evans Hooded ratswere divided into various treatment groups (N=8 to 32) and test compoundat 0.03-3.0 mg/kg or vehicle was administered orally (p.o.) by gavage ina dose volume equivalent to 5 mL/kg. One hour after dosing, baselinerectal temperatures were recorded for each rat. Rats were thenimmediately isolated in shoebox cages with ALPHA-DRY bedding. Rectaltemperatures were then recorded at 15 min, 30 min, and 45 min afterisolation (i.e., 1 hr 15 min, 1 hr 30 min, and 1 hr 45 minutes aftertest compound or vehicle administration). All experiments were conductedduring the light cycle. After completion of the behavioral portion ofthe study, each animal was killed via decapitation using a guillotineand trunk blood was collected in 5 mL vacutainer tube containing EDTAand placed on ice. The samples were then centrifuged at 3800 RPM for 10minutes and plasma was removed and placed on dry ice in an Eppendorffsample tube. Plasma samples were stored at −80° C. and later used fordetermining ACTH, corticosterone, and glucose levels. Plasma sampleswere outsourced to Anilytics, Inc. for determination of plasma levels ofACTH, coricosterone, and glucose. A Mann-Whitney U t-test (one-tailed)was used for statistical analysis of behavioral data and an unpairedt-test (one-tailed) was used for analysis of plasma ACTH,corticosterone, and glucose levels.

Results

Compound #438 was suspended in an aqueous vehicle comprised of 0.5%(w/v) methylcellulose (15 centipoises) solution.

Rats treated with Compound #438 showed an attenuation of rectaltemperature in the SIH model as described above, at 0.03 mg/kg, 0.01mg/kg, 0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg, with measured temperaturesand p values as listed in Table 21. In the Table below, the abbreviation“S.E.M.” represents the standard error of the mean and the abbreviation“N.S.” indicates that the p value indicated that any measured differencein temperature was not statistically significant.

TABLE 21 Temp. ° C. Temp. ° C. Temp. ° C. Temp. ° C. Compound (dose) 0(Basal) 15 min 30 min 45 min Vehicle Mean 37.4 38.7 38.9 38.9 S.E.M.±0.12 ±0.062 ±0.053 ±0.049 P-value Cmpd #438 Mean 37.5 38.7 38.6 38.4(0.03 mg/kg) S.E.M. 0.166 ±0.0707 ±0.139 ±0.128 P-value NS NS 0.01880.0018 Cmpd #438 Mean 37.2 38.4 38.5 38.5 (0.1 Mg/Kg) S.E.M. ±0.119±0.093 ±0.101 ±0.125 P-value NS 0.0139 0.0011 0.0098 Cmpd #438 Mean 37.438.4 38.5 38.3 (0.3 Mg/Kg) S.E.M. ±0.121 ±0.0873 ±0.0782 ±0.0853 P-valueNS 0.0068 <0.0001 <0.0001 Cmpd #438 Mean 37.1 38.4 38.5 38.2 (1.0 Mg/Kg)S.E.M. ±0.105 ±0.108 ±0.0856 ±0.109 P-value 0.0280 0.0148 <0.0001<0.0001 Cmpd #438 Mean 37.0 38.2 38.4 38.2 (3.0 Mg/Kg) S.E.M. ±0.0949±0.146 ±0.124 ±0.131 P-value 0.0121 0.0011 0.0002 <0.0001

Plasma stress hormone levels for rats treated with Compound #438 showeda 25% reduction in plasma ACTH levels at 0.3 mg/kg, the reductioncalculated to be statistically significant (P=0.0170). Changes in theplasma levels of corticosterone were not statistically significant.

EXAMPLE 73 Tissue Distribution Assay

Procedure

Male Long-Evans Hooded rats weighing 180 to 200 grams at the time ofpurchase were obtained from Charles River Laboratories (Portage, Mich.).Upon arrival, the animals were group housed four per cage in quarantinefor 5 days in wire-mesh cages at an ambient temperature of 21 to 23° C.with an automated 12/12 hour light/dark cycle and ad libitum access towater and a commercial rodent chow. The rats were then transferred to ageneral housing room for a one-week acclimation with housing andenvironmental conditions, and 12/12 hour light/dark cycle conditions.Animals were fasted overnight (18 hours) prior to experiment.

On the day of experiment, two Long-Evans Hooded rats were treated orallywith a vehicle (0.5% methylcellulose) and eight rats were treated orallywith 10.0 mg/kg of Compound #438. Five hours after drug administration,each treated animal was killed via decapitation using a guillotine,trunk blood was collected and the following tissues were harvested foranalysis of compound distribution in the following tissues/systems: (1)brain regions including the cortex, cerebellum, hypothalamus andhippocampus, (2) heart, (3) lung, (4) kidney, (5) liver, (6) spleen, (7)adrenal glands, (8) small intestines, (9) large intestines, (10) muscle,as well as (11) whole blood and (12) plasma.

Whole blood and plasma samples were prepared for analysis as follows.400 μL of acetonitrile containing 1 μM internal standard (propranolol)was added to 200 μL of plasma or whole blood to precipitate proteins.Samples were centrifuged at 5000 g for 5 minutes and supernatant removedfor analysis by LC-MS. 400 μL of water was added to adjust samplesolvent strength and prevent peak splitting. Calibration standards wereprepared by adding appropriate volumes of stock solution directly intoplasma and treated identically to collected plasma samples. LC-MSanalysis was performed using MRM for detection of characteristic ionsfor each test compound and internal standard.

Tissue samples were prepared for analysis as follows. Individual tissuesamples were extracted with 2 mLs of ethanol if the tissue weight was 1gram or less. A volume of ethanol in milliliters equal to twice theweight in grams was added if the tissue weight was greater than 1 gram.The extracts were centrifuged to precipitate solids and the supernatantwas transferred to clean Eppendorf tubes. 200 μL of this was transferredto autosampler vials and 20 μL of acetonitrile containing 1 μM internalstandard (propranolol) was added for analysis by LC/MS. Calibrationstandards were prepared using an equivalent volume of tissue extract at2 ml per gram from undosed or vehicle dosed animals. The extracts frombrain tissue were concentrated in order to achieve lower detectionlimits (<1 nM). For these, 20 μL of 1 uM propranolol in acetonitrile wasadded to 700 μL of extract and blown to dryness under nitrogen. Thesewere then reconstituted in 100 μL of 1:1::acetonitrile:water andanalyzed by LC/MS. Calibration standards were prepared in blank extractand treated exactly as samples.

Measured values within the various samples were as listed in Table 22and 23, for vehicle and Compound #438 treated rats, respectively.Results are reported in μmoles/kg or ng/g as appropriate converting thesample concentrations based on extraction solvent/tissue ratio. Theseunits are on the same scale as μmoles/l or ng/ml as typically reportedfor plasma and can be used for comparison. Detection of analytes down to0.005 μmoles/kg were typical for the LC-MS used.

TABLE 22 Vehicle (Control) Animal 9 Animal 10 (Vehicle) (Vehicle) μMμM/kg μM μM/kg Cortex 0.000 0.000 0.000 0.000 Cerebellum 0.000 0.0000.000 0.000 Hypothalamus 0.000 0.000 0.000 0.000 Hippocampus 0.000 0.0000.000 0.000 Heart 0.000 0.000 0.000 0.000 Lung 0.000 0.000 0.000 0.000Liver 0.000 0.000 0.000 0.000 Spleen 0.000 0.000 0.000 0.000 Kidney0.000 0.000 0.000 0.000 Adrenal Glands 0.000 0.000 0.000 0.000 Lrintestine 0.000 0.000 0.000 0.000 Sm Intestine 0.011 0.027 0.000 0.000Muscle 0.000 0.000 0.000 0.000 Plasma 0.000 0.000 Whole Blood 0.0000.000

TABLE 23 Compound #438 Tissue Concentration μM μM/kg μM μM/kg μM μM/kgμM μM/kg Animal 1 Animal 2 Animal 3 Animal 4 Cortex 0.0062 0.030 0.00470.020 0.0047 0.030 0.0026 0.0130 Cerebellum 0.0402 0.161 0.014 0.0900.0189 0.140 0.0045 0.0350 Hypothalamus 0.0124 0.413 0.0055 0.367 0.00640.427 0.0062 1.2400 Hippocampus 0.0195 0.650 0.0021 0.070 0.0009 0.0300.0140 0.2550 Heart 2.036 4.072 2.485 5.144 2.346 4.692 1.664 3.328 Lung5.821 15.119 4.737 12.632 5.153 13.741 4.361 11.629 Liver 6.664 13.2576.409 12.785 4.632 9.294 3.879 7.758 Spleen 9.140 25.389 7.232 17.8577.163 23.106 5.207 13.703 Kidney 3.747 7.546 4.031 8.062 4.123 8.0273.841 7.570 Adrenal Glands 0.967 24.175 0.988 28.229 1.289 28.644 1.08831.086 Lg intestine 4.518 9.036 12.478 29.019 30.593 59.694 2.231 6.562Sm Intestine 21.836 53.916 27.120 84.750 17.359 48.219 13.898 38.077Muscle 0.919 1.814 0.688 1.371 0.791 1.560 0.651 1.280 Plasma 0.4190.426 0.360 0.289 Whole Blood 0.166 0.147 0.135 0.088 Animal 5 Animal 6Animal 7 Animal 8 Cortex 0.0038 0.017 0.0023 0.010 0.0055 0.025 0.01390.062 Cerebellum 0.0026 0.019 0.0101 0.067 0.0138 0.095 0.0102 0.068Hypothalamus 0.0030 0.200 0.0036 0.360 0.0101 0.673 0.0027 0.180Hippocampus 0.005 0.200 0.002 0.010 0.0065 0.217 0.0019 0.190 Heart1.785 3.471 2.478 4.878 1.572 2.977 2.083 4.261 Lung 3.533 7.438 5.29020.346 5.655 15.930 6.189 11.902 Liver 4.006 7.861 5.090 10.180 5.88710.398 5.677 11.120 Spleen 6.730 19.229 7.742 26.697 8.062 29.859 9.20528.766 Kidney 3.993 7.791 4.718 9.523 4.109 7.645 4.750 8.782 AdrenalGlands 1.075 26.875 1.487 59.480 1.267 42.233 1.946 64.867 Lr intestine24.916 56.627 9.584 26.622 33.756 68.194 5.070 9.941 Sm Intestine 16.74341.858 14.131 56.524 25.408 72.594 13.018 39.448 Muscle 0.917 1.7540.977 1.954 0.882 1.707 1.509 3.006 Plasma 0.183 0.174 0.268 0.470 WholeBlood 0.469 0.266 0.061 0.093

EXAMPLE 74 Oral Formulation

As a specific embodiment of an oral composition, 100 mg of the compound#438 is formulated with sufficient finely divided lactose to provide atotal amount of 580 to 590 mg to fill a size O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A pharmaceutical dosage form selected from the group consisting oftablets, pills, capsules, powders, granules, sterile parenteralsolutions, parenteral suspensions, metered aerosol or liquid spray,drops, ampoules and suppositories comprising a compound of the formula(I)

wherein R⁰ is selected from the group consisting of

each R^(A) and R^(B) is independently selected from the group consistingof hydrogen and C₁₋₄alkyl; each R^(C) and R^(D) is independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl; each R^(E)is independently selected from the group consisting of hydrogen andC₁₋₄alkyl; X is —NR¹R²; each R¹ and R² is independently selected fromthe group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈alkoxy,C₁₋₈alkoxycarbonyl, cycloalkyl, cycloalkyl-C₁₋₄alkyl, partiallyunsaturated carbocylyl, partially unsaturated carbocyclyl-C₁₋₄alkyl,aryl, arC₁₋₄alkyl, arC₁₋₄alkoxy, —C(O)—C₁₋₆alkyl, —C(O)-aryl,—C(O)-arC₁₋₄alkyl, —C(O)O-cycloalkyl, —C(O)O-aryl, —C(O)O-arC₁₋₄alkyland —C(O)O-(partially unsaturated carbocyclyl); wherein the C₁₋₈alkyl,cycloalkyl, partially unsaturated carbocyclyl, aryl or arC₁₋₈alkylgroup, whether alone or part of a substituent group, is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, trifluoromethyl,trifluoromethoxy, nitro, cyano, —C(O)—C₁₋₄alkyl, C₁₋₄alkoxycarbonyl,N(R^(E))₂, N(R^(E))₂—C₁₋₄alkyl, N(R^(E))—C(O)C(CH₃)₃,—C₁₋₄alkyl-N(R^(E))—C(O)O—C₁₋₄alkyl and —N(R^(E))—C(O)O—C₁₋₄alkyl, aryl,aryloxy, cycloalkyl, heteroaryl, aryl substitutedheteroarylaminosulfonyl or C₁₋₆alkylthio; R³ is aryl; wherein the arylis optionally substituted with one or more substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^(E))₂; n is aninteger from 0 to 2; R⁴ is selected from the group consisting ofhydroxy, C₁₋₄alkyl and hydroxy substituted C₁₋₄alkyl; m is an integerfrom 0 to 1; L¹ is selected from the group consisting of C₁₋₆alkyl andC₃₋₆alkenyl; wherein the double bond of the C₃₋₆alkenyl group is atleast one carbon atom removed from the attachment point to the N atom;and wherein the C₁₋₆alkyl or C₃₋₆alkenyl group is optionally substitutedwith one to two substituents independently selected from hydroxy,fluoro, C₁₋₆alkyl, fluorinated C₁₋₆alkyl or C₁₋₆alkoxy;

is selected from the group consisting of phenyl, naphthyl andacenaphthyl; p is an integer from 0 to 5; R⁵ is selected from the groupconsisting of hydroxy, carboxy, halogen, C₁₋₆alkyl, hydroxy substitutedC₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, NR¹R², trifluoromethyl,trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO—NR¹R², —SO₂—NR¹R² and—C(O)—NR¹R²; q is 0; R⁶ selected from the group consisting of-(L²)₀₋₁-R⁷; L² is selected from the group consisting of —C₁₋₆alkyl-,-C₂₋₄alkenyl-, -C₂₋₆alkynyl-, —O—, —S—, —NH—, —N(C₁₋₄alkyl)-,—C₁₋₆alkyl-O—, —C₁₋₆alkyl-S—, —O—C₁₋₆alkyl-, —S—C₁₋₆alkyl-,—O—C₂₋₆alkyl—O—, —S—C₂₋₆alkyl-S—, —SO₂—, —SO₂NH—, —SO₂N(C₁₋₄alkyl)-,—NH—SO₂—, —N(C₁₋₄alkyl)-SO₂—, —C(O)—O— and —O—C(O)—; R⁷ is selected fromthe group consisting of aryl, partially unsaturated carbocyclyl,cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, partiallyunsaturated carbocyclyl, cycloalkyl, heteroaryl or heterocycloalkylgroup is optionally substituted with one or more substituentsindependently selected from hydroxy, carboxy, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, nitro, cyano, N(R^(E))₂, trifluoromethyl, trifluoromethoxy,C₁₋₄alkoxycarbonyl, —SO₂—N(R^(E))₂ and —C(O)—N(R^(E))₂; or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 2. The pharmaceutical dosage form of claim 1 whereinin the compound of formula (I) R⁰ is selected from the group consistingof

each R^(C) and R^(D) is independently selected from hydrogen andC₁₋₄alkyl; X is —NR¹R²; R¹ is selected from the group consisting ofhydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, aryl, arC₁₋₄alkyl,arC₁₋₄alkyloxy, cycloalkyl-alkyl and C(O)—C₁₋₄alkyl; wherein theC₁₋₄alkyl, aryl, arC₁₋₄alkyl or cycloalkyl group, whether alone or partof a substituent group, is optionally substituted with one to threesubstituents independently selected from halogen, hydroxy, carboxy,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, N(R^(E))₂,N(R^(E))₂—C₁₋₄alkyl, N(R^(E))—C(O)OC(CH₃)₃, nitro, trifluoromethyl,trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl,1-phenyl-pyrazol-2-yl-aminosulfonyl or C₁₋₄alkylthio; R² is selectedfrom the group consisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy,cycloalkyl, cycloalkyl-C₁₋₄alkyl, aryl, arC₁₋₄alkyl, arC₁₋₄alkyloxy,partially unsaturated carbocyclyl, partically unsaturatedcarbocyclyl-C₁₋₄alkyl, —C(O)—C₁₋₄alkyl, —C(O)-aryl, —C(O)—arC₁₋₄alkyl,—C(O)O-cycloalkyl and —C(OO)—C₁₋₄alkyl; wherein the C₁₋₄alkyl, aryl,arC₁₋₄alkyl, partially unsaturated carbocyclyl or cycloalkyl group,whether alone or part of a substituent group, is optionally substitutedwith one to three substituents independently selected from halogen,hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, N(R^(E))₂,N(R^(E))₂—C₁₋₄alkyl, (CH₃)₃COC(O)—N(R^(E))—C₁₋₄-alkyl, nitro, cyano,trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl,cycloalkyl, 1-phenyl substituted heteroaryl-aminosulfonyl,—C(O)—C₁₋₄alkyl or C₁₋₄alkylthio; R³ is aryl; wherein the aryl isoptionally substituted with one to three substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R^(E))₂; n is aninteger from 0 to 1; L¹ is C₁₋₄alkyl; wherein the C₁₋₄alkyl group isoptionally substituted with one to two substituents independentlyselected from hydroxy, fluoro, C₁₋₄alkyl, fluorinated C₁₋₄alkyl orC₁₋₄alkoxy; R⁵ is selected from the group consisting of hydroxy,carboxy, halogen, C₁₋₄alkyl, C₁₋₄alkoxy, nitro, cyano, N(R^(E))₂,trifluoromethyl, trifluoromethoxy, C₁₋₄alkoxycarbonyl, —SO—N(R^(E))₂,—SO₂— N(R^(E))₂ and —C(O)— N(R^(E))₂; or a pharmaceutically acceptablesalt thereof.
 3. The pharmaceutical dosage form of claim 1 wherein inthe compound of formula (I) R⁰ is selected from the group consisting of

each R^(A), R^(B), R^(C) and R^(D) is hydrogen; X is —NR¹R²; R¹ isselected from the group consisting of hydrogen, C₁₋₄alkyl,C₁₋₄alkoxycarbonyl, arC₁₋₄alkyl and C(O)—C₁₋₄alkyl; wherein theC₁₋₄alkyl or aryl group, whether alone or part of a substituent group,is optionally substituted with one to two substituents independentlyselected from carboxy, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,N(R^(E))₂ or N(R^(E))—C(O)OC(CH₃)₃; R² is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, cycloalkyl, aryl,arC₁₋₄alkyl, arC₁₋₄alkyloxy, partially unsaturated carbocyclyl,partially unsaturated carbocyclyl-C₁₋₄alkyl, cycloalkyl-C₁₋₄alkyl,—C(O)arC₁₋₄alkyl, —C(OO)-cycloalkyl and —C(O)O—C₁₋₄alkyl; wherein theC₁₋₄alkyl, aryl, arC₁₋₄alkyl, partially unsaturated carbocyclyl-orcycloalkyl group, whether alone or part of a substituent group, isoptionally substituted with one to three substituents independentlyselected from halogen, hydroxy, carboxy, C₁₋₄alkyl, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, N(R^(E))₂, N(R^(E))₂—C₁₋₄alkyl,(CH₃)₃CO—C(O)—N(R^(E))—C₁₋₄alkyl, nitro, trifluoromethyl,trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl,1-phenyl-pyrazol-2-yl-aminosulfonyl or C₁₋₄alkylthio; R³ is aryl;wherein the aryl group is optionally substituted with one or moresubstituents independently selected from halogen; n is 0; L¹ isC₁₋₄alkyl; R⁵ is selected from the group consisting of halogen,C₁₋₄alkyl and trifluoromethyl; or a pharmaceutically acceptable saltthereof.
 4. The pharmaceutical dosage form of claim 1 wherein in thecompound of formula (I) R⁰ is selected from the group consisting of—CH₂—CH(OH)—CH₂—X and —CH₂—CH₂—CH(OH)—CH₂—X; X is —NR¹R²; R¹ is selectedfrom the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl,t-butyl, amino-n-propyl, dimethylaminoethyl, benzyl, phenylethyl,4-methyl-benzyl,

2-(3,4-dimethoxy-phenyl)ethyl, 3-methyl-phenyl, ethoxy-carbonyl-methyl,2-amino-2-methoxycarbonyl-ethyl, t-butoxycarbonyl and

R² is selected from the group consisting of hydrogen, methyl, methoxy,ethyl, carboxy-methyl, ethoxycarbonylmethyl, 2,2,2,-triluoroethyl,ethoxy, dimethylaminoethyl, t-butoxycarbonylamino-ethyl, n-butyl,t-butyl, n-propyl, 3-hydroxy-n-propyl, 3-methoxy-n-propyl,methylamino-n-propyl, dimethylamino-n-propyl, di(n-butyl)amino-n-propyl,t-butoxycarbonylamino-n-propyl, 3-phenyl-n-propyl,3-(2-pyridyl)-n-propyl, t-butoxycarbonyl, cyclopropyl, phenyl,4-fluorophenyl, 4-methylphenyl, 3,4-dimethoxyphenyl, 2-aminophenyl,4-biphenyl, 2-ethoxyphenyl,4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-cyclohexylphenyl,4-(aminoethyl)phenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl,—CH(CH₃)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl,2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl,4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl), 3-iodobenzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl,3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl,4-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 2,3-dimethoxybenzyl,2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl,2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl,2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl,3,4-difluorobenzyl, 3,5-di(trifluoromethyl)benzyl,4-(dimethylamino)benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl,2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl,2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl,1-adamantanyl, 1-adamantanyl-methyl, 1-naphthyl, 1-naphthyl-methyl,1-phenyl-2-(t-butoxycarbonyl)ethyl, —C(O)—C(OCH₃)(CF₃)-phenyl,—C(O)O-(2-isopropyl-5-methyl-cyclohexyl),

2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl,2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl and2-phenyl-cyclopropyl; R³ is selected from the group consisting of phenyland 4-fluorophenyl; L¹ is selected from the group consisting of —CH₂—,—CH(CH₃)— and —CH₂CH₂—;

is selected from the group consisting of 1-acenaphthenyl,R-1-acenaphthenyl, S-1-acenaphthenyl, phenyl, 1-naphthyl, 2-naphthyl and1,2,3,4-tetrahydro-naphthyl; R⁵ is selected from the group consisting ofchloro, methyl, n-propyl and trifluoromethyl; or a pharmaceuticallyacceptable salt thereof.
 5. The pharmaceutical dosage form of claim 4wherein in the compound of formula (1) X is —NR¹R²; R¹ is selected fromthe group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl,t-butyl, dimethylaminoethyl, benzyl, phenylethyl,

3-methyl-phenyl, 2-(3,4-dimethoxyphenyl)-ethyl, ethoxycarbonyl-methyl,dimethylamino-ethyl and 2-amino-2-methoxycarbonyl-ethyl; R² is selectedfrom the group consisting of hydrogen, methyl, methoxy, ethyl,ethoxycarbonyl-methyl, 2,2,2-triluoroethyl, ethoxy, dimethylaminoethyl,n-butyl, t-butyl, n-propyl, di(n-butyl)amino-n-propyl,3-phenyl-n-propyl, cyclopropyl, phenyl, 4-fluorophenyl, 4-methylphenyl,2-aminophenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl,3,4-dimethoxyphenyl, 4-biphenyl, 2-ethoxyphenyl, 4-(aminoethyl)-phenyl,benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl,3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 3-iodobenzyl, 2-fluorobenzyl,3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl,3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl,4-trifluoromethoxybenzyl, 4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl,2,4-dichlorobenzyl, 3 ,4-dichlorobenzyl, 2,4-difluorobenzyl,2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl,2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl,2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl,3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl, 2-phenylethyl,2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl,2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, adamantanyl,1-adamantanyl-methyl, 1-naphthyl, 1-naphthyl-methyl,

2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl,2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl; L¹ is selected fromthe group consisting of —CH₂— and —CH₂—CH₂—;

is selected from the group consisting of 1-acenaphthenyl,R-1-acenaphthenyl, S-1-acenaphthenyl, phenyl-and 1-naphthyl; p is aninteger from 0 to 2; or a pharmaceutically acceptable salt thereof. 6.The pharmaceutical dosage form of claim 5 wherein in the compound offormulate (I) R¹ is selected from the group consisting of hydrogen,methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl,phenylethyl, 2-(3,4-dimethoxyphenyl)-ethyl, dimethylamino-ethyl,ethoxycarbonyl-methyl,

R² is selected from the group consisting of hydrogen, methyl, methoxy,ethyl, ethoxycarbonyl-methyl, ethoxy, dimethylaminoethyl, n-butyl,n-propyl, di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl,3-(2-pyridyl)-n-propyl, cyclopropyl, phenyl, 4-fluorophenyl,4-methylphenyl, 2-aminophenyl, 3,4-dimethoxyphenyl,4-(t-butoxycarbonylamino-ethyl)-phenyl, 4-biphenyl, 2-ethoxyphenyl,4-(aminoethyl)-phenyl, benzyl, benzyloxy, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl,4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl,3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl,3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 3-nitrobenzyl,4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl,3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl,2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl,2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 1-adamantanyl,1-adamantanyl-methyl, 1-naphthyl, 1-naphthyl-methyl

2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl,2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl; p is an integerfrom 0 to 1; R⁵ is selected from the group consisting of methyl,n-propyl and trifluoromethyl; or a pharmaceutically acceptable saltthereof.
 7. The pharmaceutical dosage form of claim 4 wherein in thecompound of formula (I) R⁰ —CH₂—CH(OH)—CH₂—X; X is —NR¹R²; R¹ isselected from the group consisting of hydrogen,2-(3,4-dimethoxyphenyl)-ethyl, 1-(3,4-dimethoxyphenyl)-n-ethyl andamino-n-propyl; R² is selected from the group consisting of hydrogen,methyl, n-butyl, 3-hydroxy-n-propyl, 3-methoxy-n-propyl,methylamino-n-propyl, dimethylamino-n-propyl,t-butoxycarbonylamino-n-propyl,N-methyl-N-t-butoxycarbonyl-amino-n-ethyl, 3-nitrobenzyl,4-methoxycarbonyl-benzyl and —CH(CH₃)-phenyl; R³ is selected from thegroup consisting of phenyl and 4-fluorophenyl; L¹ selected from thegroup consisting of —CH₂— and —CH₂CH₂—;

is selected from the group consisting 1-naphthyl, 1-acenaphthenyl,R-1-acenaphthenyl and S-1-acenaphthenyl; p is an integer from 0 to 1; R⁵is methyl; or a pharmaceutically acceptable salt thereof.
 8. Thepharmaceutical dosage form of claim 7 wherein in the compound of formula(I) R¹ is selected from the group consisting of hydrogen,1-(3,4-dimethoxyphenyl)-n-ethyl and amino-n-propyl; R² is selected fromthe group consisting of hydrogen, methyl, n-butyl, 3-hydroxy-n-propyl,3-methoxy-n-propyl, methylamino-n-propyl, dimethylamino-n-propyl,N-methyl-N-t-butoxycarbonyl-amino-n-ethyl, 3-nitrobenzyl,4-methoxycarbonyl-benzyl and —CH(CH₃)-phenyl;

is selected from the group consisting 1-naphthyl, 1-acenaphthenyl,R-1-acenaphthenyl and S-1-acenaphthenyl; or a pharmaceuticallyacceptable salt thereof.
 9. The pharmaceutical dosage form of claim 7wherein the compound is selected from the group consisting of 8-(R)acenaphthen-1-yl-3-(3-amino-2-(S)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one; 8-(R)acenaphthen-1-yl-3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;8-(R)-Acenaphthen-1-yl-3-(3-dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one;3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;3-(3-Dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-hydroxy-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-methylamino-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one;3-[3-(3-Dimethylamino-propylamino)-2-(R)-hydroxy-propyl]-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneand pharmaceutically acceptable salts thereof.
 10. The pharmaceuticaldosage form of claim 1 wherein the compound is3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneand pharmaceutically acceptable salts thereof.
 11. A pharmaceuticalcomposition suitable for oral administration comprising3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-oneand pharmaceutically acceptable salts thereof and pharmaceuticallyacceptable carriers.
 12. The pharmaceutical composition of claim 11wherein the dosage form is a solid dosage form.
 13. The pharmaceuticalcomposition of claim 12 where in the solid dosage form is selected fromthe group consisting of pills, tablet, caplet, capsule granules andpowders.
 14. The pharmaceutical composition of claim 11 wherein thedosage form is a liquid dosage form selected from the group consistingof solution, syrups, elixirs, emulsions and suspensions.